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Curative Cancer Chemotherapy
Emil Frei III
Cancer Res 1985;45:6523-6537.
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[CANCER RESEARCH 45, 6523-6537,
December 1985]
Position Paper
Curative Cancer Chemotherapy1
Emil Frei III
Dana Farber Cancer Institute, Boston, Massachusetts 02115
ABSTRACT
Cancer chemotherapy provides variably effective treatment for
the majority of forms of human cancer and curative treatment
for some 12 categories of cancer. Curative treatment is defined
as the proportion of patients who survive beyond the time after
which the risk of treatment failure approaches zero, i.e., the
disease-free survival plateau. This progress has resulted from a
closely integrated scientific effort, including drug development,
pharmacology, preclinical modeling, experimental design with
respect to clinical trials, quantitative criteria for response, and a
series of clinical trials (initially in children with acute lymphocytic
leukemia) in which the importance of complete remission, of
dose and schedule, of sequencing chemotherapeutic agents, of
pharmacological sanctuaries, and particularly of combination
chemotherapy was studied. The principles derived from these
studies, particularly those relating to combination chemotherapy,
resulted in curative treatment for disseminated Hodgkin's dis
ease, non-Hodgkin's lymphoma, pediatrie solid tumors, testicular
cancer, and limited small cell lung cancer. Many patients with
certain stages of solid tumors, such as breast cancer and osteogenic sarcoma, are at high risk of having disseminated micro
scopic disease. Experimental studies indicate that treatment
which is only partially effective against macroscopic disease is
much more effective against microscopic tumors. Therefore
chemotherapy is administered immediately following control of
the primary tumor in patients at high risk of having disseminated
microscopic disease, a treatment known as adjuvant chemo
therapy. This program has been highly successful in increasing
the cure rate in patients with pediatrie solid tumors and in
prolonging disease-free survival in patients with premenopausal
breast cancer. Given dissemination of the technology, it is esti
mated that 15,000-30,000
patients per year are potentially
curable in the United States. Curability of cancer by chemother
apy generally is inversely related to age, i.e., the above tumors
are most common in children and young adults. There are new
and promising treatment strategies, such as neoadjuvant chem
otherapy and autologous bone marrow transplantation. The rev
olution in molecular and cellular biology is providing an increase
in targets, rationale, and opportunity for more effective and novel
chemotherapeutic approaches.
INTRODUCTION
This paper will describe the major conceptual and clinical
investigational advances that have led to the cure of certain
Received 3/14/85; revised 7/25/85, 8/15/85; accepted 9/10/85.
1A position paper of the American Association for Cancer Research, Inc.,
commissioned by the Association's Scientific and Public Affairs Committee.
Requests for reprints for both individual and bulk orders should be addressed
to: American Association for Cancer Research, Inc., Temple University School of
Medicine, West Building, Room 301, Philadelphia, PA 19140.
CANCER
RESEARCH
forms of cancer by chemotherapy. Basic science has contributed
to this progress in terms of the synthesis, development, and
preclinical studies of the active chemotherapeutic agents. How
ever, the major thrust of this presentation will deal with the
integrated clinical and basic science efforts that have taken these
tools (active chemotherapeutic agents) and constructed progres
sively effective and finally definitive treatment for a number of
neoplastic disease categories. It will be organized primarily by
disease category, historical sequence, and three strategies: (a)
chemotherapy only; (b) adjuvant chemotherapy; and (c) neoad
juvant chemotherapy.
The term "cure" is a sensitive one and subject to several
definitions. In a strict sense, a representative sample of patients
with a given disease must survive a normal life span. In an
operational sense, this would be counterproductive, since it
would take, for example, 60 years to determine whether a given
treatment program for childhood leukemia was curative. Some
physicians deliberately avoid using the word "cure," preferring
the expression "long-term disease-free survival." We think this
inappropriate if the evidence for cure is compelling (see below).
The well-being and compliance of patients are substantially
improved if they are aware that they are being treated with
curative intent. To the extent that physicians and investigators
are ambivalent with respect to the use of the term "cure," patients
and the medical community will be skeptical. One of the obstacles
to progress in cancer therapy generally and in cancer chemo
therapy specifically has been the presence of such skepticism.
For most categories of tumors, the cure rate can be securely
and operationally defined as the disease-free survival plateau
(69,168). Thus following potentially definitive treatment, the risk
of relapse is major at an early stage and decreases with time;
then there is a point in time (1 to 4 years, depending upon the
kinetics of the tumor) after which the risk of relapse is minimal
(<10%). Thus the disease-free survival from that point is essen
tially flat (plateau). Confidence in the delivery of curative treat
ment by this definition is based on the number of patients and
the duration of survival on that plateau. Breast cancer is the only
major exception to the application of this operational definition
for cure. This is because the risk of failure in breast cancer, while
it decreases with time, continues beyond 5 and even 10 and 15
years (93). Thus except for breast cancer, the disease-free
survival plateau will define cure in this paper.
While declining mortality from a tumor must be the ultimate
parameter of curative treatment, its operational utility is limited.
Thus the time required from the introduction of curative treatment
for a given tumor to the recognition and confirmation that curative
treatment has, in fact, been delivered is substantial. Additional
time is required for the transfer of such technology to the
community such that a decrease in mortality occurs. For exam
ple, curative combination chemotherapy for Hodgkin's disease
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was introduced in 1963 (37, 62). Since the risk period for failure
after treatment of Hodgkin's disease is 4 years, it was 7 years
(1970) before the first full publication appeared which indicated
the probability that Hodgkin's disease was curable by chemo
therapy (38). Further follow-up of that study and other studies
provided extension and confirmation of the results so that, by
the mid-1970s, it was generally appreciated that patients with
disseminated Hodgkin's disease could be treated with curative
intent. However, not until the mid-1970s and later was there a
significant decline in mortality for Hodgkin's disease based on
national mortality statistics. This time lag was shorter for testicular cancer, which is a more dynamic disease; I.e., the diseasefree survival plateau begins as early as 1 year following treat
ment. The time lag is much longer for diseases such as breast
cancer, ovarian cancer, and small cell lung cancer, wherein the
dynamics of the disease are much slower and/or the cure rates
attributable to chemotherapy substantially lower. It is not sur
prising, therefore, that in the main the curative treatment which
developed between 1970 and 1975 may not yet have had an
impact on national mortality statistics. Indeed, curative treatment
developed after that time and, particularly after 1980, might not
yet be wholly recognized as such because there has been
insufficient time for the development of a secure disease-free
survival plateau (60).
CHEMOTHERAPY
Gestational Choriocarcinoma
This tumor produces a marker, HCG,2 in the serum, which in
the individual patient is a precise measure of tumor burden,
including microscopic tumor burden, down to as few as perhaps
1000 cells. It was observed in the 1950s that antifolates inter
fered with the estrogen effect on the oviduct and that serum
human chorionic gonadotropin decreased in a patient receiving
methotrexate (98, 119).
In 1956, after a pilot clinical pharmacological study was ob
served to diminish HCG, an intensive intermittent methotrexate
program was developed for gestational Choriocarcinoma (119).
A prompt decrease in human chorionic gonadotropin followed by
a decrease in tumor size was observed in the first and subse
quently in almost all patients. As complete clinical remissions
were achieved, treatment was continued in an effort to reduce
the microscopic tumor burden. This could be measured by serum
HCG levels and such treatment was continued for one to two
courses beyond the point where the HCG had reached normal
levels (99,118).
This observation has been widely confirmed, and currently
methotrexate alone, or more commonly methotrexate combined
with actinomycin D, produces cure rates in over 90% of patients
with low or intermediate tumor burdens at the time of diagnosis.
Even in patients with high tumor burden, as measured clinically,
2 The abbreviations used are: HCG, human chorionic gonadotropin; ALL, acute
lymphocytic leukemia; CMS, central nervous system; VAMP, vincristine, amethopterin, Oncovin, and prednisone; ara-C, 1-/3-o-arabinofuranosylcytosine;
MOMP,
mustargen, Oncovin, methotrexate, and prednisone; MOPP, mustargen, Oncovin,
procarbazine, and prednisone; ABVD, Adriamycin, bleomycin, vinblastine, and
dacarbazine; DHL, diffuse histiocytic lymphoma; CHOP, cycloheximide, hydroxydaunorubicin, Oncovin, and prednisone; AML, acute myelogenous leukemia; cisplatin, c/s-diamminedichloroplatinum(ll);
VBP, vinblastine, bleomycin, and cisplatin;
CMF, cyclophosphamide, methotrexate, and fluorouracil; PROMACE-MOPP, pred
nisone, methotrexate, Adriamycin, cyclophosphamide, etoposide, mustargen, vin
cristine, prednisone, and procarbazine.
CANCER
RESEARCH
radiographically, and by tumor markers, cure rates of greater
than 60% can be achieved in the majority of cases (118,156).
A benign, but potentially malignant, precursor of Choriocarci
noma is the hydatidiform mole, which when locally invasive in
the uterus requires hysterectomy. Surgical removal of the uterus
compromises the quality of life in young women. Accordingly
methotrexate has been used in selected patients and has been
found to be highly effective in providing a nonsurgical approach
to eradicating invasive and metastatic moles. Subsequent fertility
and normal pregnancy in such patients have not been impaired
(104).
ALL in Children
The sequential studies leading to the development of curative
treatment for ALL deserve attention, since many of the studies
relating to experimental design, criteria for response, the impor
tance of preclinical modeling, cytokinetics, pharmacology, and
particularly the importance of dose, schedule, and combination
chemotherapy were major targets of quantitative and often orig
inal studies in this disease (57).
Chemotherapeutic Agents
The folie acid antagonists were introduced in 1947; the glucocorticoids and adrenocorticotrophic hormone in 1951; 6-mercaptopurine in 1953; vincristine and cyclophosphamide in 1961;
and, more recently, asparaginase, anthracyclines, and 1-0-Darabinofuranosylcytosine.
In 1955, a quantitative, prospective (scientific) clinical trial was
first applied to cancer (66), specifically to acute lymphocytic
leukemia in children, with emphasis on precisely defining the
following in advance: the therapeutic hypothesis; selection of
patients; treatment strategy and tactics; quantitative criteria for
response; and major biostatistical input concerning experimental
design, including, where appropriate, randomization and stratifi
cation, quality control, and mechanisms for data collection and
analysis (66,196).
Complete Remission
Complete remission consists of the complete clinical and hematological disappearance of disease. It was found in the above
quantitative study that the most powerful discriminant for prog
nosis in terms of survival was the attainment of complete remis
sion (66, 71).
Increasing the Complete Remission Rate
Given the importance of complete remission, emphasis was
given to increasing the complete remission rate. This was most
readily achieved with combination chemotherapy. Single agents
produced complete remission rates varying from 20 to 50%,
whereas combinations of Chemotherapeutic agents, particularly
vincristine and prednisone, produced complete remission rates
of 80-90% (63, 67,167). These studies were the first to under
score the importance of combination chemotherapy.
The fundamental rationale for combination chemotherapy is
tumor cell heterogeneity, indicating the need for multitargeted
therapy (116). Agents with qualitatively different mechanisms of
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action are, for the most part, not associated with cross-resist
ance. Thus combination chemotherapy reduces the risk of emer
gent drug-resistant tumor cells (116). In parallel studies where
dose was investigated as an independent variable, the doseresponse curve was steep for both tumor and host (83). Agents
which had nonmyelosuppressive dose-limiting toxicity could be
used in combination at full doses and hence accrue the effective
ness of the combination without compromise in dose (59). In
retrospect, the ultimate rationale for combination chemotherapy
is the pragmatic one, i.e., essentially all highly effective and
curative chemotherapeutic regimens represent combinations.
Combination chemotherapy has become a highly sophisticated
basic and clinical research discipline and has been the subject
of in-depth reviews (8).
Treatment during Remission
With the high complete remission rate achieved as above,
survival was somewhat improved, but all patients relapsed from
remission. Accordingly treatment during remission was essential.
Experimentalists, particularly Skipper ef al. (171), had demon
strated the first order kinetic effect of chemotherapeutic agents.
Given a homogeneous population of cells, the fractional reduction
of tumor cells was constant, independent of tumor burden.
Hence complete remission of the tumor represented "the tip of
the iceberg" in an exponential sense and substantially further
treatment (treatment during remission) was required to eradicate
microscopic disease (63).
The signal studies addressed to the biology of the microscopic
tumor burden as defined by chemotherapy were as follows.
Prolongation of Remission. It was demonstrated that the
antileukemic agent 6-mercaptopurine significantly prolonged the
duration of complete remission as compared to a placebo. This
established the importance of treatment during remission and
also represented the first "adjuvant" study (70).
Effect of Schedule. Methotrexate was the best single agent
for treatment during remission, but relapse invariably occurred.
Experimental studies in transplanted leukemias indicated that
the intermittent administration of methotrexate was superior to
daily administration of methotrexate (83). A study comparing
twice weekly methotrexate with daily methotrexate in ALL in
complete remission indicated a marked prolongation of remission
with the former program (167). This established the premise that
schedule could influence the therapeutic index and started the
trend towards intermittent treatment. While the rationale for this
approach was obscure at the time, it probably relates to the
recently demonstrated evidence that in vitro drug resistance to
methotrexate occurs much more readily with continuous treat
ment as compared to intermittent selection pressure (166).
Dose. In a randomized comparative study, it was found that
a 2-fold difference in dose of agents used during remission
resulted in a significant improvement of duration of remission for
the higher dose (142).
Combinations. As with remission induction, combinations of
chemotherapeutic agents, including, in particular, intermittent
methotrexate and continuous 6-mercaptopurine administration,
significantly prolonged the duration of remission as compared to
single agents (64, 103).
CANCER
RESEARCH
Meningeal Leukemia
With the above high rate of complete remission and increasing
duration of remissions, there occurred an increasing frequency
of meningea! leukemia in patients in complete remission to the
point where >50% of patients relapsed with meningea! leukemia
(49). Detailed clinical studies, as well as studies of an experimen
tal model, indicated that the central nervous system was involved
with microscopic disease in the majority of patients at the time
of diagnosis (78). Pharmacological studies indicated that the
antileukemic agents used systemically did not pass the bloodbrain barrier (146). Thus the central nervous system was a
pharmacological sanctuary wherein leukemia could progress in
patients in otherwise complete systemic remission.
Brain irradiation and intrathecally administered methotrexate
had definite, albeit limited, effectiveness in patients with overt
meningeal leukemia. It was therefore applied in quantitative
studies immediately following remission induction in an effort to
eradicate microscopic disease (so-called CNS prophylaxis). This
resulted in a reduction of meningeal leukemia from in excess of
50% of patients in complete remission to <10% in most and
<5% in some studies (3, 4, 67,141).
The VAMP Program
A number of experimental studies indicated, and clinical stud
ies implied, that optimal treatment would consist of maximal,
intensive, intermittent "up front" combination chemotherapy. This
led to the development of the VAMP program, which produced
a high complete remission rate and long durations of remission
but was limited by the absence of CNS prophylaxis (63,73, 91).
Nevertheless, the VAMP program served as a stimulus and
prototype for subsequent combination chemotherapy studies,
such as those in the lymphomas.
The Cure of ALL
The integration of the aforementioned strategies, i.e., combi
nation chemotherapy for complete remission induction; followed
by CNS prophylaxis; followed by combination systemic treatment
during remission, resulted in a long-term disease-free survival
(cure rate) in 40-50% of patients (102,103,141,160).
The Last 10 Years. The addition of asparaginase and/or an
anthracycline to vincristine and prednisone for remisssion induc
tion produces complete remission rates approaching 100% and
further prolongs the duration of remission (102,141,160).
The use of asparaginase i.m. weekly and Adriamycin during
the first 6 months of remission, on a background of 6-mercap
topurine and intermittent methotrexate administration, adapted
to prognostic factors has resulted in disease-free survival for
standard-risk patients approaching 100% and 70% for poor-risk
patients, with an overall survival of 85% (161).
Intensive multiple combination "up front" therapy, involving the
intensive use of multiple agents (vincristine, prednisone, daunorubicin, Adriamycin, asparaginase, dexamethasone, cyclophosphamide, and ara-C) during the first 8 weeks of therapy, has
also provided disease-free survival curves in the range of 7080% (95).
CNS prophylaxis with radiotherapy has been associated with
mild (about 10%) deficits in mentation, attention span, and other
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aspects of central nervous system function (78, 133, 157). This
has led to investigation of alternative approaches to CNS pro
phylaxis. High-dose methotrexate with leucovorin rescue sup
plies therapeutic levels of methotrexate to the cerebrospinal fluid,
providing effective prophylaxis of CNS leukemia, particularly in
standard-risk patients. The issue as to its relative effectiveness
compared to brain irradiation with intralumbar intrathecally ad
ministered methotrexate is to some extent determined by risk
factors (56,143,157).
Prognostic Factors and Tumor Biology. Prognostic factors
such as age, pretreatment white blood cell count, and mediastinal
mass have provided for the stratification of patients into highand low-risk groups.
These interrelated prognostic factors have been variably pow
erful, depending upon the treatment. More recently, a more
fundamental pathobiological classification has been made pos
sible by immunological phenotyping. These findings are consist
ent with the thesis that T-cell leukemias, and probably also the
B-cell leukemias, represent monoclonal expansion of a given
differentiation step. Cytogenetic studies are consistent with the
clonal origin of leukemia and show reciprocal translocations that
may affect the activity of oncogenes. Molecular biological studies
of immunoglobulin gene rearrangement indicate monoclonal ar
rest in patients with B-cell disease. Such changes demonstrate
the B-cell origin, even of tumors that lack surface B-cell immu
nological phenotypes (113, 134, 149). Almost all patients can
now be categorized by cell lineage and differentiation levels.
Various categories may demonstrate major differences in re
sponse to treatment and prognosis.
otrexate (16, 69). Full doses of these agents produced response
in 60% of the patients, whereas the random sample of patients
who received one-half of the full dose had marginal antitumor
effects. A simiiar steep dose-response relationship held for sys
temic toxicity.
MOMP. Given the aforementioned and the ALL experience,
the four-drug combination chemotherapy study (MOMP) was
Acute Lymphocytic Leukemia in Adults
use of single agents, occurred rapidly and, most importantly,
they were durable with an overall cure rate with very adequate
follow-up of 40-50% (38, 39).
Acute lymphocyte leukemia in adults resembles high-risk ALL
in children in terms of clinical behavior, immunological phenotyp
ing, and cytogenetics. The application of the aforementioned
principles for ALL in children to ALL in adults include, in particular,
the use of an anthracycline and/or asparaginase with vincristine
and prednisone to achieve a high complete remission induction
rate and the use of combination chemotherapy during remission.
This includes alternation between cell cycle-nonspecific and cell
cycle-specific agents; the use of an anthracycline early in remis
sion; and related approaches. Disease-free survival plateaus
have been achieved in 40-60% of patients, a range approacning
that of high-risk ALL in children. This is particularly true of the
younger adult patients who tend to have more favorable prog
nostic factors (7,107,125,165).
Disseminated Hodgkin's Disease
Alkylating agents were found to be effective in producing tumor
regression in Hodgkin's disease in World War II. Methotrexate
and vinblastine were observed to be effective by the early 1960s,
and vincristine and prednisone were separately found to be
effective and, importantly, nonmyelosuppressive.
In comparative studies, Vinca alkaloids and alkylating agents
were found individually to produce partial responses in 50% and
complete responses in 10% of patients. Responses were slow
in developing and relatively brief (2-4 months) (23).
Dose. This first randomized trial wherein dose was an inde
pendent variable was conducted in Hodgkin's disease and nonHodgkin's lymphoma patients using alkylating agents and meth
CANCER
RESEARCH
initiated in 1963 (37, 62,197). It was based on the rationale that:
(a) the agents had different mechanisms of action and presum
ably were not cross-resistant; (b) two of the agents were non
myelosuppressive and thus dose modifications for the combi
nation should be minimal; (c) cytokinetic modeling and experi
mental in vivo studies of first order kinetic effect of single agents,
drug resistance, and combination chemotherapy suggested that
agents with the aforementioned activity in combination might be
capable of achieving a 10-12-log cell kill, which might be suffi
cient to eradicate the Hodgkin's disease (59,63,72); and (d) the
drugs were given in combination in 10-14-day courses every 4
weeks based on experimental and clinical evidence that myeloid
and immunological recovery occurred during that interval. Such
intermittent treatment tended to be superior to continuous treat
ment not only for methotrexate but also for alkylating agents,
and this effect perhaps can be generalized in experimental
systems (97).
MOPP. In 1964, procarbazine, a nonclassical alkylating agent
which had proved effective for the treatment of Hodgkin's dis
ease in Europe and in preliminary
was substituted for methotrexate
MOMP and the MOPP programs
in 60-80% of the patients. These
studies in the United States,
(resulting in MOPP). Both the
produced complete remission
remissions, in contrast to the
Clinical trials indicated that maintenance treatment with MOPP
did not increase the cure rate, but that the duration of treatment
with MOPP could be operationally determined by the rapidity
with which complete remission occurred and the results of
intensive (including pathological) staging prior to treatment ces
sation (191).
ABVD. Subsequent to the mid-1960s, additional agents were
found to be active in patients with Hodgkin's disease, including
dacarbazine, Adriamycin, and bleomycin. Accordingly, Adriamycin-based combinations, such as ABVD, were developed. These
combinations produced variable complete remission rates in
patients refractory to MOPP in the United States, but in large
quantitative studies in Italy they produced response and cure
rates comparable to those achieved with MOPP (15). In a com
parative study, MOPP alternated with ABVD produced a 75%
disease-free survival estimate, compared to 50% for MOPP only
(15). Noncontrolled studies of the MOPP-ABVD regimen with or
without radiation to pretreatment sites of bulk disease have
produced similar cure rates (15,173).
Studies of treatment failure in patients achieving complete
remission with MOPP indicated a remarkable pattern of relapse.
As might be predicted from cytokinetic analyses, relapses oc
curred quite reproducibly at pretreatment sites of bulk disease.
This might have major implications for treatment, particularly
with respect to follow-up radiotherapy (68,192).
Late Effects. In addition to the acute toxic effects that are
well known to cancer chemotherapy, the Hodgkin's chemother-
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apy experience produced two chronic effects worthy of note.
Acute myelogenous leukemia occurred with a latent period of at
least 2 years following MOPP treatment in 5% of patients. On
the basis of experimental studies, including mutagenicity and in
vivo studies, it is concluded that procarbazine in particular, and
alkylating agents as well, are the major contributors to this
leukemogenesis. Of note is the fact that ABVD and programs
for ALL which do not use procarbazine or alkylating agents do
not show an increase in secondary acute myelogenous leukemia.
With a relatively large number of active agents for Hodgkin's
disease, it should be possible to structure treatment programs
with high cure rates which factor out agents known to be potent
mutagens and carcinogens (21, 35).
The above figures for complete response and cure rates (6080%) for Hodgkin's disease relate to patients with advanced
disease, i.e., Stages 1MBand IV. A number of clinical trials indicate
that combination chemotherapy plus limited-field radiotherapy is
highly effective for patients with Stages I and IIA disease and
that combinations of chemotherapeutic regimens with radiother
apy may improve disease-free survival in certain intermediate
stages of Hodgkin's disease (154). The interpretation of these
studies, however, has been complicated by improvement in
salvage therapy. Thus total nodal radiotherapy plus MOPP is
superior to MOPP alone in certain studies of intermediate-stage
Hodgkin's disease in terms of the initial disease-free survival, but
the difference disappears with long-term follow-up because sal
vage therapy with radiotherapy and ABVD is superior in patients
who have received one rather than two modalities as initial
treatment (154).
Non-Hodgkin's Lymphoma
novel recent contributions to the combination chemotherapy of
DHL were: (a) cytokinetically based adjustments in the duration
of courses of treatment in the PROMACE-MOPP program; and
(b) the demonstration that high-dose methotrexate with leucovorin rescue maintained the full antitumor activity of methotrex
ate but (with appropriate pharmacological monitoring) resulted in
much reduced toxicity, thus making it ideal for combined therapy
(40, 55, 61, 169, 175). Other combinations, such as COMLA
(ara-C, vincristine, methotrexate with rescue, and cyclophospha
mide) also produced good results. It is difficult to compare these
programs across institutions, but at least four of them, (PRO
MACE-MOPP, M-BACOP, COP-BLAM, CHOP ±bleomycin ±
VP16) produce initial complete remission rates approaching 80%
and long-term disease-free survival plateaus of 50-60% (18,55,
115,169).
Non-Hodgkin's
group of diseases; it has been the subject of a sequence of
hematopathologic classifications, of which the Rappoport has
been the most durable and the working formulation the most
recent. Pathologically the intermediate or large cell group with a
diffuse pattern is cytokinetically the most aggressive and also
the most subject to curative treatment with chemotherapy. How
ever, while the cure rate for DHL is in the range of 50%, it is
substantially lower for the less common forms such as diffuse
poorly differentiated lymphoma and diffuse mixed cell lymphoma.
Approximately one-half of non-Hodgkin's lymphomas com
prise the nodular, indolent category. While these respond initially
to single agent or combination chemotherapy with good remis
sion rates and reasonable durability, the force of relapse and
failure is constant over time. With the possible exception of
nodular mixed lymphoma, there is no evidence that present
chemotherapy is curative.
Shortly after the demonstration that combination chemother
apy could produce high initial complete response rates in Hodg
kin's disease, the MOPP program, with cyclophosphamide as
the alkylating agent (C-MOPP), was used in the treatment of
non-Hodgkin's lymphoma. In diffuse histiocytic lymphoma, a 4050% complete response rate was achieved. Essentially all of
these patients remained in remission, with a cure rate of approx
imately 40% (36). This reaffirmation of the importance of an initial
complete remission led to a sequence of studies of combination
chemotherapy designed to (a) increase the complete remission
rate and (b) improve the durability of complete remissions.
Adriamycin had major single agent activity in non-Hodgkin's
lymphoma, including particularly DHL; the CHOP regimen, which
includes Adriamycin, produced response rates of 60% and longterm disease-free survivals in the range of 30-40% (110,128).
Burkitt's Lymphoma
Whether epidemic in Africa or endemic in the United States,
Burkitt's lymphoma is curable by chemotherapy. Burkitt dem
onstrated that single-agent cyclophosphamide was curative for
patients with Stage I and II disease. Relatively high cure rates
have been achieved with combination chemotherapy for Stage I
and II disease, with lower but definite cure rates for Stage III
disease (17,195).
Similarly lymphoblastic lymphoma, which is a T-cell disease
occurring primarily in adolescents and young adults, has cure
rates in the range of 40-70%, with treatment based on programs
similar to those for high-risk acute lymphocytic leukemia and/or
Subsequent studies resulted in further modifications of com
bination chemotherapy designed to: (a) add effective agents
without compromising the dose rate of the basic CHOP compo
nents (e.g., bleomycin, high-dose methotrexate with rescue); (b)
control the proliferate thrust between courses of chemotherapy
for this aggressive tumor (distribute the administration of vincristine and high- or intermediate-dose methotrexate with rescue to
the interface between combination chemotherapy courses); (c)
add other agents of known effectiveness but which might com
promise the dose of cyclophosphamide and Adriamycin (VP16,
procarbazine); and (cf) cycle combinations of chemotherapeutic
agents (PROMACE-MOPP), with a rationale comparable to that
of MOPP-ABVD for Hodgkin's disease. Perhaps the two most
CANCER
RESEARCH
lymphoma is an extraordinary heterogeneous
diffuse histiocytic lymphoma (184).
Acute Myelogenous Leukemia
Supportive Care. The dose-response curve for most chemo
therapeutic agents is steep, and myelosuppression is the most
common form of dose-limiting toxicity. Therefore the develop
ment of blood product support and antibiotics for the control of
thrombocytopenia and for the prevention and treatment of infec
tions has had a major impact on the effectiveness of chemother
apy in terms of safety and therefore in terms of dosing, with
respect to both unit dose and interval between treatments. Bone
marrow transplantation may be viewed, in part, as the ultimate
in bone marrow support. Much of the research in blood product
support and marrow transplantation began with and had its
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major impact on AML (reviewed in Ref. 88).
Remission induction. ara-C was the first agent with substan
tial activity in AML. When given daily, complete response rates
in the range of 10-15% were achieved (47). Skipper ef al. (172)
in a series of elegant experimental studies in mouse L1210
leukemia demonstrated a marked influence of schedule on the
therapeutic index, probably related to the cytokinetics of the
tumor as compared to the bone marrow. In summary, they found
that courses of ara-C which lasted twice the generation time of
the leukemic cells provided substantial cytoreduction and such
courses could be repeated without compromise every 4 days,
an interval sufficient to allow for complete recovery from myelo-
definite effectiveness have been identified; these include 6-mercaptopurine or thioguanine, azacytidine, probably vincristine and
prednisone and, more recently, amsacrine and mitoxantrone.
Accordingly combinations of agents which were rotated at ap
propriate intervals to minimize the emergence of drug-resistant
lines were used (183).
Based on the above, several studies emphasizing high doses
of ara-C for remission induction and/or early intensification and
suppression in the mouse. Comparative cytokinetics of AML and
the normal marrow in humans indicated that the appropriate
extrapolation would be 5-day courses of continuous infusion,
with a 9-10-day interval between such courses (139, 172). In
comparative and noncomparative studies, it was found that such
intermittent treatment produced significantly higher complete
remission rates (35-40%), as compared to daily treatments
(15%) and significantly prolonged the duration of remission (10).
The activity of the anthracyclines was demonstrated (181).
Daunorubicin is probably superior to Adriamycin because of
somewhat lesser side effects relating to the gastrointestinal tract
(190). When daunorubicin was combined with 5-day courses of
ara-C, remission rates of 50% were achieved. Based on cytokinetic considerations, 7-day infusions of ara-C were studied, and
it was found that 7 days of continuous infusion of ara-C plus
three daily injections of daunorubicin (the 7 & 3 program) pro
duced complete remission rates of 70% (145). Substantial com
plete remission rates were achieved in patients over 50 years of
age. As with ALL 15 years earlier, the stage was set for ap
proaches involving treatment during remission designed to pro
long the duration of remission and ultimately to eradicate the
microscopic tumor burden.
Early Intensification. The rationale for early intensification
was based on the fact that the potential for cytoeradication was
maximal immediately after complete remission induction when a
microscopic, minimally drug-exposed tumor burden existed, and
before the ravages of clonal evolution developed, particularly
specific or pleiotropic drug resistance (96,121).
Single, highly intensive courses of ara-C given during remission
as high as 50% in pediatrie AML patients (22, 183). In adults,
late relapses still occur, but survival plateaus in the range of
20% have been achieved in a number of studies (28, 111, 126,
144,182).
AML Prognostic Factor Analysis. Using multistep regression
analysis over a series of studies, prognostic factor profiles for
complete remission induction and for duration of remission mea
sured from different time points were identified (76). Of consid
erable interest was the fact that prognostic profiles for complete
remission induction differed substantially from those for duration
of remission (112). With such information, patients could be
segregated with respect to treatment regimens; I.e., patients
with the expectation of poor response to conventional treatment
could be started on new treatment. Perhaps the most compelling
has been the correlation of cytogenetic abnormalities with prog
nosis. For example, inversion in chromosome 16 in AML is
associated with an improved survival (median survival time, 25
months). Trisomy 8 has an intermediate prognosis (median sur
vival time, 10 months), but complex chromosomal changes indic
ative of two or more stem lines and therefore clonal evolution
and heterogeneity have a markedly adverse effect on prognosis
(median survival time, 2.5 months) (194).
AML Biochemical Pharmacology. Detailed studies of the
biochemical pharmacology of ara-C in patients with AML have
provided significant variations which may predict prognosis on
the one hand and influence the choice, dose, and duration of
ara-C on the other hand. These include studies of ara-C triphosphate pool concentrations and half-times, DMA polymerase inhi
bition, and ara-C incorporation into DNA (114,159,106).
In the latter studies, it was observed that ara-C at high
concentrations produced chain termination of DNA synthesis,
precluding recovery of DNA synthesis, and therefore causing
major cytotoxicity. At low concentrations in the HL-60 cell line,
chain elongation was slowed, and differentiation of this human
acute promyelocytic leukemia line in vitro was demonstrated.
This was confirmed by morphological and myeloid antigen stud
ies and was associated with a marked decrease in expression
of the myc gene. Thus clinical trials designed to induce matura
tion have been undertaken (186).
Very high doses of ara-C have, in preliminary studies, pro
duced substantial remission rates in patients with refractory AML
and lymphoma (22).
induction were attended not only by a high complete remission
rate but also by a prolonged duration of unmaintained remissions
(22,25,52,179,187,188).
ara-C exhibited a steep concentration
viability curve against AML cells in culture (127). Such was also
true in in vivo experimental animal studies. Moreover because of
the cell cycle specificity and the presumed lack of stem cell effect
of ara-C, bone marrow recovery tended to occur quickly (within
3 weeks) and increasing doses, which increased the magnitude
of myelosuppression, did not increase the duration of myelosuppression (158, 183,188).
Late Intensification. The rationale for late intensification with
combination chemotherapy 6-12 months after treatment during
remission related to the expectation that a minimal tumor burden
might exist at this time and thus provide maximal opportunity for
cytoeradication (11). In addition, there is evidence for delayed
cytokinetic recovery of tumor cells following treatment. Such
cytokinetically active cells should be more susceptible to chem
otherapy (137).
In addition to the two primary agents, agents with limited but
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often including the sequencing of other active agents were
undertaken during remission. These trials, in younger patients,
produced complete remissions approaching 80% with continu
ous, complete remission curves (long-term disease-free survival)
Testicular Cancer
In the 1950s, it was demonstrated that actinomycin D pro
duced a significant response rate in patients with disseminated
nonseminomatous testicular cancer. Combinations of actinomy-
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effective antiemetics for the control of cisplatin-induced emesis
ein D, methotrexate, and chlorambucil were equally and possibly
more effective than was actinomycin D alone, and some 5-10%
of patients thus treated had long-term complete remissions
consistent with cure (120).
In the mid-1960s, vinblastine was found to produce partial
responses in a substantial proportion of patients. It was dem
onstrated that higher doses of vinblastine, particularly when
given in combination with bleomycin, produced significant com
plete response rates, some of which were durable (163).
In preclinical toxicological studies, cisplatin was demonstrated
to be selectively toxic to the male gonad. Clinical trials indicated
substantial activity against refractory testicular cancer (100). The
stage was set for multidrug therapy.
As with all of the aforementioned studies, major attention to
clinical pharmacology, toxicology, dose scheduling, and duration
of treatment was essential before the optimal program, VBP,
was identified. These drugs have differing dose-limiting toxicity
and thus can be used in combination at full dose. It has now
been widely confirmed that this combination produces a high
initial complete remission rate and durable remissions in 50-70%
of patients in most studies and in upwards of 90% of patients in
some studies (45, 46, 75, 180). Cure is generally achieved after
four courses of VBP. Patients either show evidence of refractory
disease by that time or more commonly are free of clinical and
marker evidence of disease and do not relapse. Testicular cancer
is an aggressive disease such that relapse of patients in complete
remisssion after cessation of treatment usually occurs within the
first year, and it almost always occurs by 24 months.
Partial responses to VBP can be converted in many instances
to complete responses by surgical extirpation of regressed but
persisting lesions. The durability of such remissions approaches
that of de novo complete remissions (41). This important treat
ment strategy is consistent with other evidence that high-risk
sites of relapse (pretreatment sites of bulk disease and incom
pletely regressed lesions) after chemotherapy may be definitively
controlled by surgery and/or radiotherapy.
This highly effective and curative combination chemotherapy
for advanced testicular cancer raises the question as to its utility
as adjuvant therapy. Patients with Stage I disease have a 10%
risk, and those with Stage II disease have a 50% risk for relapse
after local therapy. It was found in both comparative and noncomparative studies that two courses of VLB following local
treatment produced essentially a 100% cure rate for Stage I and
II disease. In order not to treat patients who do not require
treatment, a sample of patients with locally controlled Stage I
and II disease was followed closely, particularly by the use of
tumor markers and chest film. Early relapse was identified. The
cure rates for such patients with four courses of VLB approach
100%. Thus adjuvant chemotherapy is probably not required,
except in high-risk patients or in patients where compliance is
suspect (45).
The development of radioimmunoassays
for measuring nano-
gram quantities of human chorionic gonadotropin and other testis
tumor markers has been of critical importance in the evaluation
and particularly in the tactics of treating and following patients
with testicular cancer.
Major advances have been achieved in the control of central
nausea and vomiting induced by chemotherapy. This is a major
problem with respect to cisplatin and often precluded the delivery
of adequate doses. The development of new and increasingly
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RESEARCH
was an important step in the evolution towards curative chem
otherapy for testicular cancer.
The above figures apply to patients with classical, nonseminomatous testicular cancer. Patients with extremely high hor
mone titers and tumor burdens and patients with extragonadal
germ cell primary tumors do not respond as well, and different
treatment strategies are indicated.
ADJUVANT CHEMOTHERAPY
The above studies and results relate to the use of chemother
apy against established clinically evident disseminated disease.
Evidence in experimental in vivo tumors indicates that a given
chemotherapy which is marginally effective against macroscopic,
clinically overt disease may be highly effective and indeed cura
tive against a microscopic burden of the same tumor (82, 170).
Essentially all studies relating to the science of tumor biology,
including cytokinetics, heterogeneity, and tumor neovascularization, strongly support the thesis that the potential for cytoeradicative chemotherapy should be far greater against the
microscopic (<109) tumor burden as compared to clinically evi
dent (>1011) tumor burden in humans (80, 96). There are many
clinical circumstances wherein the nature and the extent of the
primary tumor are such that a high probability exists that dissem
inated micrometastases are present at the time when local
control is achieved with surgery and/or radiotherapy. In such
circumstances where chemotherapy has proven of moderate but
limited benefit in clinically overt metastatic disease, such treat
ment has been moved "up front" immediately behind local control
in an effort to eradicate micrometastatic disease. This is called
adjuvant chemotherapy, i.e., adjuvant to local treatment with
surgery and/or radiotherapy. Historically the first studies of ad
juvant chemotherapy and, indeed, many of the principles of
adjuvant chemotherapy were initially applied, developed, and
subjected to quantitative clinical trials in the pediatrie solid tu
mors.
Pediatrie Solid Tumors
This heterogeneous group of relatively rare tumors includes
Wilm's tumor, embryonal rhabdomyosarcoma, and Ewing's sar
coma. These tumors have been the subject of a common multidisciplinary definitive treatment strategy. Actinomycin D added
to localized treatment of Wilm's tumor with surgery and/or
radiotherapy increases the cure rate from 40 to 80% and was
the first demonstration of the effectiveness of adjuvant chemo
therapy (50). It is in these tumors that neoadjuvant chemother
apy; i.e., chemotherapy used initially to reduce local disease,
was first shown to be effective in increasing the subsequent
curability of radiation and/or surgery (33). For Wilm's tumor,
actinomycin D and vincristine are the most effective combination;
for embryonal rhabdomyosarcoma and Ewing's tumor, vincris
tine, actinomycin D, and cyclophosphamide, with or without
Adriamycin, are the most effective (26, 89).
In a series of comparative studies, it has been established
that: (a) localized treatment, including surgery and/or radiation,
may be used initially if local control can be achieved; (b) chemo
therapy, as above, should be applied initially if stage reduction
is required for local control by surgery and/or radiotherapy; and
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(c) chemotherapy following surgery and/or radiotherapy is re
quired in the majority of patients to eradicate microscopic and,
in some instances, macroscopic métastases.As a generalization
for these tumors, radiation and surgery would be expected to
cure some 30%; and with multimodality therapy, including chem
otherapy, the figures approach 80% (26). Neuroblastoma is less
responsive, although recent evidence with combined modality
therapy featuring alkylating agents indicates that durable com
plete remissions can be achieved, particularly in Stage III patients
(150).
Breast Cancer
Breast cancer is the most common cause of death from cancer
in women. The risk of ultimate treatment failure and death in
patients with breast cancer (and in other neoplastic diseases as
well) can be determined by evaluating the extent of the disease
following diagnosis (staging). The principal prognostic discrimi
nant for patients with localized disease is axillary lymph node
involvement. Thus local treatment with surgery and/or radiother
apy provides a 75% 10-year survival for node-negative patients.
For node-positive patients, the respective figures are 15-35%
(54, 93).
The lack of a disease-free survival plateau and therefore an
operational definition of cure for breast cancer has been pre
sented. Thus, the risk for failure after treatment of primary breast
cancer, while it decreases with time, continues beyond 5 and
even 10 and 15 years. Nevertheless some of the randomized
trials of adjuvant chemotherapy for breast cancer show signifi
cant differences in favor of chemotherapy in long-term diseasefree and overall survival (up to 10 years) (12,14, 53, 92).
Axillary node-positive breast cancer patients are at high risk
of having disseminated micrometastatic disease, as evidenced
by the fact that usually within 1 to 3 years, but often later, the
majority (70-90%) of patients who will relapse do so with clini
cally overt disease. Clinically overt metastatic disease can be
treated effectively with chemotherapy or hormonal therapy, but
treatment failure eventually occurs and the patient is destined to
die of the disease.
There are a number of chemotherapeutic agents, including
alkylating agents, antimetabolites such as methotrexate and
fluorouracil, and Adriamycin, which individually produce response
rates in 25-50% of patients. Combinations of chemotherapeutic
agents in comparative and noncomparative studies produce
higher response rates (in the range of 50%), with combinations
involving Adriamycin being perhaps superior; i.e., they produce
response rates in the range of 60-70% (93). This degree of
responsiveness of clinically overt disease (high tumor burden
disease) would suggest that such treatment applied to low tumor
burden disease (micrometastases immediately following control
of the primary tumor in patients with Stage II disease, adjuvant
chemotherapy) might be capable of eradicating the tumor. In
experimental transplanted tumors, there is definitive and widely
confirmed evidence that a chemotherapy program which is only
partially effective against a high tumor burden has a much higher
probability of being curative against a low tumor burden (81, 82,
170). Moreover the effectiveness, in terms of producing tumor
regression in the high tumor burden setting, correlates with
curability for the same treatment in the low tumor burden setting.
As a result of the above, adjuvant chemotherapy for patients
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RESEARCH
with node-positive breast cancer in studies using modern tumor
biological, chemotherapeutic, pharmacological, and experimental
design concepts and techniques was begun in the early 1970s.
These early studies, where chemotherapy was compared to no
treatment, indicate that, particularly for premenopausal women,
disease-free survival is significantly improved as a result of
adjuvant chemotherapy (12, 14, 53, 92). Combination chemo
therapy, usually CMF or close analogues thereof, is superior to
single-agent therapy (31,93). The initial concept of maintenance
treatment carried out for 2 years is probably inappropriate,
inasmuch as there is experimental (Skipper) and now clinical
evidence that more short-term treatment is equally effective.
Thus where duration of treatment was an independent variable,
CMF for 6 months proved as effective as CMF for 12 months
(176), and a combination of Adriamycin and cyclophosphamide
for 4 months was as effective as the same regimen delivered
over an 8-month period (94).
Retrospective analysis of clinical studies (13), as well as nu
merous experimental studies, suggest that dose, or more prop
erly dose rate, correlates with the capacity of the treatment
regimen to control micrometastatic disease; however, some
other clinical studies have not confirmed this. Thus high priority
must be given to prospective studies where dose is the inde
pendent variable. Hormone therapy, when added to chemother
apy, in postmenopausal, estrogen receptor-positive women, in
relatively short-term studies, further improved disease-free sur
vival (52). Whether combinations including Adriamycin are su
perior to those without and whether relatively recently introduced
strategies, such as the rotation of non-cross-resistant combina
tions, will improve effectiveness remain to be determined.
The most important, but also the most difficult, question is
whether adjuvant chemotherapy has significantly increased the
cure rate. Two of the best designed studies, which also have
the longest follow-up (10 years), are the melphalan versus control
(NSABP) (53) and the CMF versus control (Milan) (14) studies.
Here disease-free survival, particularly in premenopausal pa
tients, is clearly superior in patients receiving chemotherapy.
More important, overall survival is significantly superior at the
11-year (maximum) follow-up point (a 20% improvement) for
premenopausal patients. This improvement in survival appears
early and progresses with time. Two other major studies dem
onstrate improved disease-free and overall survival for adjuvant
chemotherapy in both pre- and postmenopausal patients with 8and 15-year follow-up (79, 136). Several reports, however, do
not confirm the effectiveness of adjuvant chemotherapy in post
menopausal patients.
Small Cell Lung Cancer
This cytokinetically aggressive tumor is responsive to a variety
of chemotherapeutic agents. For patients with clinically limited
disease (;'.e., disease limited to the chest), complete response
rates of 40-60% can be achieved with combination chemother
apy (29, 123).
Relapse in the central nervous system is common, occurring
in 25% or more of patients. This can be reduced to <5% by
cranial irradiation early in complete remission (123). A more
common site of relapse in patients entering complete remission
is at the pretreatment site of bulk disease in the chest. Irradiation
here will also reduce the risk of local, thoracic relapse from 60%
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to as low as 15-25% (105). Remission induction with combina
tion chemotherapy and particularly the rotation of combinations
of chemotherapeutic agents during remission for up to 1 year
have markedly improved disease-free and overall survival for this
disease (29, 124). While the majority of patients relapse, some
10-20% of patients with limited, small cell lung cancer will
continue disease free beyond 3 or 4 years (29,123,124). While
the risk of relapse markedly decreases after 2 years, 19 of 97
patients disease free at 2.5 years subsequently relapsed, 2 after
8 years (6).
Osteogenic Sarcoma
Local control can almost always be achieved for this tumor by
amputation. Nevertheless the survival rate for the 30 years
preceding the 1970s was in the range of 20% largely because
of the development of lung métastases(74,129).
In the early 1970s, it was demonstrated that high-dose methotrexate with rescue produced réponsesin a small proportion of
patients with advanced disease and, when used as adjuvant
chemotherapy immediately following surgery, produced a dis
ease-free survival plateau of 40% (108). At about the same time,
Adriamycin was found to be comparably effective (32). The
combination of high-dose methotrexate and Adriamycin in the
adjuvant setting, particularly where dose rate of the individual
agents was preserved, produced the expected additive rate, i.e.,
disease-free survival plateaus between 50 and 60% (84). These
agents in various combinations with cisplatin and other agents
in a variety of studies produce disease-free survival plateaus in
the range of 50-70% (24), and in a more complex combination,
but featuring, in particular, high-dose methotrexate and Adria
mycin, a disease-free survival plateau of 70-80% has been
achieved (151,185).
In the mid-1970s, stimulated by the capacity of chemotherapy
to produce tumor regression, limb-preserving surgery was de
veloped. Chemotherapy before surgery, i.e., neoadjuvant chem
otherapy, often resulted in cytoreduction in the primary tumor,
providing an improved opportunity for local bone tumor resection
and endoprosthesis insertion (43,109,152).
In addition, preoperative chemotherapy provides an opportu
nity to evaluate the effectiveness of high-dose methotrexate with
or without Adriamycin against overt disease and to correlate this
with subsequent survival which is a function of the capacity of
chemotherapy to control micrometastatic disease. It was found
that cytoreduction by chemotherapy of the primary tumor was
correlated with eradication of micrometastatic disease, mainly in
the lungs, when the same chemotherapy was continued after
control of the primary tumor. Accordingly response of the primary
tumor was used as a measure of effectiveness of chemotherapy,
and major adjustments were made in the adjuvant program for
patients in whom primary tumor regression was suboptimal (151,
185).
Osteogenic sarcoma is a rare disease, such that comparative
studies are difficult, if not impossible, to conduct in single insti
tutions. Clinicians at the Mayo Clinic noted a progressive increase
in disease-free survival of osteogenic sarcoma into the early
1970s in the absence of adjuvant chemotherapy. Therefore, they
conducted a study in the mid-1970s, wherein patients, following
control of the primary tumor, were randomly allocated to highdose methotrexate with leucovorin rescue or to an untreated
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RESEARCH
control group (42). In a relatively small sample of patients (only
30% of eligible patients agreed to randomization), there was no
difference between the two groups, both having disease-free
survival plateaus in the range of 40% (42).
Does adjuvant chemotherapy indeed improve the cure rate of
patients with osteogenic sarcoma, or have we been a victim of
the vagaries of early diagnosis, evaluation, and other factors
which might change the natural history? To answer this question,
two randomized studies were undertaken, one a single institution
(UCLA) study, and the other in a cooperative group (POG).
Following surgical control of the primary tumor, patients were
randomly allocated to combination chemotherapy, featuring highdose methotrexate with rescue and Adriamycin, or were allo
cated to no-treatment control groups. These studies have been
completed, and a highly significant difference in 2-year diseasefree survival in favor of the chemotherapy arm was observed in
both studies (44, 122).
Soft-Tissue Sarcomas in Adults
Metastatic soft-tissue sarcoma is responsive to Adriamycin,
which produces partial responses in approximately 30% of pa
tients (138). In most studies, this is increased to 40 to 60%
by the addition of dimethyltriazinoimidazolecarboxamide,
cyclophosphamide, and perhaps vincristine (9, 85, 86). From 10 to
15% of such patients with overt metastatic soft-tissue sarcoma
achieved complete remission, about one-third of which (3 to 4%
of the total) are durable (189).
Adriamycin and Adriamycin combinations were therefore eval
uated in the adjuvant treatment of high-grade soft-tissue sarco
mas, where local control had been achieved. In randomized
studies, both positive and negative results have been reported
(2,155). Improved overall survival for all patients in recent years,
probably because of better control of the primary tumor through
integrated surgery and radiotherapy, has complicated the design
and interpretation of adjuvant studies (174). A large controlled
intergroup study of the role of adjuvant chemotherapy in softtissue sarcomas is ongoing.
Gastric and Rectal Carcinoma
Gastrointestinal carcinoma is generally poorly responsive to
chemotherapy. While response rates of up to 40% for gastric
carcinoma
using combination
chemotherapy
have been
achieved, the figures for the remainder of nonesophageal gas
trointestinal carcinomas are in the range of 20% (132). Neverthe
less major multiinstitutional adjuvant chemotherapy trials have
been undertaken.
For Stage II, a regional gastric carcinoma, a multiinstitutional
study has compared fluorouracil plus methylcyclohexylnitrosourea to a no-treatment control arm following surgery. There was
a significant (approximately 20%) improvement in disease-free
and overall survival in the adjuvant arm (30). However, negative
studies have been reported (101 ).
In a study of high-risk localized rectal carcinoma conducted by
the same multiinstitutional group (Gastrointestinal Tumor Study
Group), the addition of postoperative radiotherapy increased
local control as compared to a randomized control group. The
addition of fluorouracil plus methylcyclohexylnitrosourea
pro
duced a further and significant (20%) improvement in disease-
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free and overall survival (131 ). These studies of gastric and rectal
carcinoma await confirmation and extension.
Bone Marrow Transplantation
Bone marrow transplantation exploits the dose effect, both for
radiotherapy and for chemotherapy (usually cyclophosphamide).
It has been most effective when used in patients with acute
leukemia in the minimal tumor burden setting that is present
early in complete remission (177). A low cure rate was achieved
for acute myelogenous leukemia with total body radiation only.
Cyclophosphamide, when added to total body radiotherapy,
increased the cure rate. In AML, some 50% of patients treated
early in complete remission and supported by histocompatible
bone marrow transplantation are cured (177). Thirty % die,
largely of graft-versus-host disease. Only 20% have relapse of
leukemia. Comparable figures have been achieved with combi
nations of intensive cyclophosphamide and busulfan (164). Sim
ilar programs with matched allogeneic or autologous bone mar
row (with or without chemotherapy or immunological approaches
to controlling bone marrow "contamination") have provided a
variable proportion of long-term disease-free survivors in patients
with acute lymphocytic leukemia in second or subsequent remis
sion (147,177), patients with acute myelogenous leukemia (177),
selected patients with chronic myelogenous leukemia in stable
phase (confirmed by eradication of the Philadelphia chromosome)
(51), and in patients with various types and stages of high-risk
non-Hodgkin's lymphoma (135,140).
Ovarian Cancer
Cytoreductive surgery (debulking) improves response to sub
sequent chemotherapy in terms of duration of disease control
(87). Thus, surgery plays a relatively novel role for Stage III and
IV ovarian cancer in terms of reducing the tumor burden in
preparation for systemic treatment and also is used in end
staging (second look) to determine the effectiveness of systemic
treatment following debulking. The alkylating agents have long
been known to be effective in producing tumor regression in
perhaps 50% of patients with ovarian cancer. The addition of
Adriamycin and of cisplatin has increased the overall response
rate and particularly has resulted in complete clinical tumor
regression in 40% of patients (27, 193). Up to 50% of Stage III
and IV disease patients who achieve complete clinical tumor
regression will, with end staging (second look operations), be
microscopically disease free. In those studies using this approach
with 5-year or greater follow-up, there is evidence that 15-20%
of all patients with Stage III and IV disease so treated are clinically
and microscopically disease free (27, 47,193). Whether this can
be improved upon by more effective chemotherapy (34), by more
effective initial surgery, by monitoring ovarian antigen, and by
monitoring with second-look operations, intraperitoneal chemo
therapy, and/or immunological approaches remains to be deter
mined (27, 34, 147,193).
NEOADJUVANT
CHEMOTHERAPY
primary tumor (stage reduction), such that the primary tumor
becomes operable and/or treatable with radiotherapy with cura
tive intent. In addition, disseminated micrometastatic disease,
the risk of which will depend on the primary site, type, and extent
(stage), will also be addressed initially (58). This is of importance
in view of the fact that micrometastatic disease is probably
kinetically more aggressive than overt disease and thus at con
siderable risk of mutation to drug resistance. Mutation theory,
modeling, and experimental studies suggest that the risk of
micrometastatic disease developing resistant cell lines over a
relatively short time period (several months) may be major (80,
168). To this extent, the initiation of systemic treatment in the
form of neoadjuvant chemotherapy avoids the 1- to 2-month
delay which is likely to occur if the primary tumor is treated
initially with surgery and/or radiotherapy. Neoadjuvant chemo
therapy with respect to childhood tumors and osteogenic sar
coma has already been discussed. The development of increas
ingly effective agents and combination chemotherapy for squa
mous cell carcinomas has suggested that the neoadjuvant ap
proach may be an idea whose time has come.
In head and neck cancer, in which neoadjuvant chemotherapy
is under the most intensive study, several combination regimens,
which include cisplatin, can produce initial tumor regression rates
of 70 to 90%, with complete response occurring in 20 to 50%
of patients (1, 48, 77). Following chemotherapy, such patients
are treated with surgery and/or radiotherapy with curative intent.
Whether surgery should be decreased in terms of extent of
resection and radiotherapy reduced in terms of field size and
dose because of prior tumor reduction with chemotherapy re
sponse remains controversial. What seems clear in some studies
is that survival after surgery and radiotherapy correlates with the
degree of response to neoadjuvant chemotherapy. Thus patients
who achieve complete remission after chemotherapy have rela
tively high survival rates, as compared to those who achieve
partial responses (1, 48). It remains to be determined whether
this approach will in fact increase the cure rate in patients with
advanced (Stage III and IV) head and neck cancer. Other tumors
for which neoadjuvant chemotherapy is the subject of study
include Stage III regional non-small cell lung cancer, Stage III
breast cancer, esophageal cancer, bladder cancer, anal carci
noma, and, as above, osteogenic sarcoma.
CONCLUDING AND SUMMARY
The final arbiter of advances in curative treatment for a given
disease must be reduction in national mortality attributable to
such treatment. As indicated in the introduction, it may take 5 to
20 years from the time of introduction of curative treatment to
recognize its impact on national mortality. For certain diseases
where there has been a major impact of curative cancer chem
otherapy, where such treatment has been in effect for a sub
stantial number of years, and where the disease is dynamic, a
significant reduction in mortality has, in fact, occurred. For ex
ample, this has been conclusively demonstrated for acute lym
phocytic leukemia in children, Hodgkin's disease, diffuse histio-
The improved effectiveness of chemotherapy in squamous cell
carcinoma, largely as a result of the use of platinum-based
combinations, has reopened these diseases to approaches in
volving initial chemotherapy in an effort to reduce the size of the
CANCER
RESEARCH
REMARKS
cytic lymphoma, pediatrie solid tumors, testicular cancer, and
gestational trophoblastic cancer (117,130).
A more current and therefore relevant measure of the impact
of curative treatment is presented in Table 1. Even here, the time
lag and some of the other problems mentioned in the introduction
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Table 1
refinements in surgery and radiotherapy are under development.
The in vitro tumor stem cell assay may allow for assessing
patient responsiveness to antitumor agents and thus the in-
Curability of cancer by chemotherapy (1983)
curabilityEstablishedType
Potential
dividualization and optimization of treatment (162). Basic science
studies relating to oncogene products, differentiation, immunocancerALL of
toxins, microenvironmental signals, and drug resistance, to men
(pediatrie)ALL
(2,000)3,600
tion a few, provide new targets, strategies, and tactics for the
(adult)AML
(3,600)350
(pediatrie)AML
(350)6,000
immediate future. Therapeutic ferment has led to the expectation
(adult)Breast
(4,500)41
by many experts that progress in the curative treatment of head
(premenopausal)Breast
(20,750)72,500(26,100)24,500
,500
and neck cancer, selected stages of lung cancer, esophageal
(postmenopausal)Gastric
I)Hodgkin's
(Stage
(8,085)7,100(4,260)18,005(15,188)18,005(9,315)23,000(9,315)23,000
cancer, rectal cancer, bladder cancer, anal cancer, and cervical
IIIand
(Stages
cancer may be under way.
IV)Lung,
Long-term disease-free survival (cure) for patients with cancer
cellUmitedAdvancedLymphoma,non-Hodgkin'sOvarian
small
is increasing. This has led to increasing emphasis on the quality
of life. In contrast to some chronic diseases, the vast majority of
patients cured of cancer return to full activity with little or no
(7,000)
compromise
in the quality of life. Emphasis on less radical
60-9690>80No.1,6001,4401409004,1503,9151,2133,4083,0387596,521700
tumorsTesticularTrophoblastic
Pediatrie solid
2,250(2,135)5,40025-7560>80No.1,000720704502,075001,7041,51903,7260
1,0741,94494815,230Putative%80404020201515802056510
1,6382,91694833,286
procedures for breast cancer (90) and limb preservation proce
(3,240)1,000(1,000)%50202010100040100400
diseaseTotalIncidence
dures for extremity cancers (152,153) are representative of such
efforts. The potential long-term adverse effects of chemotherapy,
)"2,000
(—
a (—), subset appropriate for curative intent chemotherapy
references, see text.
" Includes Wilms', rhabdomyosarcoma,
(see text) (3). For
Ewing's, lymphoma, and osteosarcoma.
are pertinent, but they are not as restrictive as those relating to
mortality. In the first column of Table 1 are listed the 11 (or 14 if
pediatrie solid tumors are divided into their components) tumors
which can be cured by chemotherapy (see above). The incidence
figures are the number of new patients diagnosed with that
disease in 1983 by American Cancer Society statistics (19). The
numbers in parentheses represent the subset of the total inci
dence appropriate to curative intent chemotherapy. For example,
in breast cancer, only patients with Stage II disease (<50% of
the total) are candidates for adjuvant chemotherapy.
Curability is divided into established and putative. The "estab
lished" column represents figures based on multiple studies
conducted in centers and cooperative groups which are well
established in time, numbers of patients, and confirmation. In the
"putative" column, the percentage of cure rate represents more
recent studies, the majority of which had been confirmed or are
in the process of being confirmed by ongoing studies. (For details
and references above, see text with respect to specific disease.)
While it takes time to disseminate the curative treatment tech
nology to the community, there is substantial evidence that once
such treatment is well established, it can be effectively applied
in the community (5). Hence the word "potential" relates to the
number of patients cured by multiplying percentage cured by the
number of patients treated (in parentheses under "incidence").
The total number of patients, by these estimates, comes to
15,000-30,000 per year. While this represents only approxi
mately 10% of the annual mortality from cancer, it is important
to emphasize that curative treatment by chemotherapy is in
versely related to age. Thus the diseases wherein a high cure
rate is achieved are disproportionately represented in the pedi
atrie and young adult population. Hence the overall impact on
survival is substantially greater than the figures in Table 1 indi
cate.
With rapid advances in basic tumor biology and clinical inves
tigation, it is probable that advances in curative treatment will
continue. New strategies relating to chemotherapy and hormonal
therapy, the rapidly emerging field of tumor immunology, and
CANCER
RESEARCH
VOL.
such as the increased risk of leukemia, are being intensely
studied, particularly by the deletion of those chemotherapeutic
agents which have major mutagenic and carcinogenic activity,
where this can be accomplished without significantly compro
mising the cure rates (20).
Thirty years ago it was widely held that cancer could not be
cured by chemotherapy. Ten years ago it was conceded that
tumors of hematological and embryological origin might be cu
rable, but the more common epithelial tumors would not yield to
chemotherapy. Progress has been steady and has accelerated
as such dire predictions have been progressively set aside. While
progress has been substantial and real, we still have a long way
to go. The current revolution in basic tumor biology, continuing
clinical innovations, and the interaction between the two provide
realistic optimism for continuing progress in the curative treat
ment of cancer.
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