Theoretical Concepts and the Emerging Role

of Taxanes in Adjuvant Therapy

LARRY NORTON
Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Key Words. Adjuvant · Breast cancer · Gompertzian · Log kill · Paclitaxel · Docetaxel · Herceptin

A BSTRACT
The proven benefits of adjuvant chemotherapy on important, but that dose-dense schedules may have an
disease-free and overall survival in breast cancer can advantage over conventional schedules of drug admin-
be explained by concepts of cell kill. Interventions istration. Sequential therapy may allow dose-dense

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which result in greater log kill can be expected to pro-
duce improved clinical results. The application of log-
kill concepts to human breast cancer growth, which
appears to follow Gompertzian kinetics, suggests not
only that the use of non-cross-resistant drugs is
administration of cytotoxic agents and encourage the
integration of new biological agents into combination
regimens, particularly with the taxanes. Ongoing trials
in these concepts are reviewed. The Oncologist
2001;6(suppl 3):30-35

INTRODUCTION seen in murine tumors, and hence a more sophisticated view

Evidence for the existence of occult micrometastases at
the time of diagnosis is overwhelming [1]. Equally clear is
that some form of systemic therapy is the only treatment
which may have an impact on the problem of occult disease
[2]. This paper presents certain theoretical concepts impor-
tant to our understanding of empirical data in the field of
adjuvant therapy.
At the start of the development of medical oncology,
Skipper et al. introduced the important concept of log kill [3,
4]. Although the model was based on murine tumors, it was
soon extrapolated to human systems. A fundamental concept
is that killing of cells is the ultimate determinant of outcome
in an organism harboring a cancer. The extent of cell kill pre-
dicts disease-free survival, and improved disease-free survival
translates into extended overall survival [1, 2, 5, 6].
Several methods of killing cells are relevant to the adju-
vant setting; these include hormonal manipulation through
selective estrogen receptor modulators such as tamoxifen and
(historically) hormone manipulation through oophorectomy.
However, this paper focuses on the effects of chemotherapy,
and in particular, on how active agents can be administered
together in combination and sequentially to maximize clini-
cal benefit. In this context it is important to note that the pat-
tern of growth seen in human cancers is not the same as that
is needed of cell kill and its consequences.
EXPONENTIAL GROWTH, LOG KILL,
AND CHEMOTHERAPY
Central to our understanding of tumor growth is the
expectation that cell numbers will increase exponentially, i.e.,
that numbers double and continue doubling over a certain
fixed unit of time [7]. Such a pattern of growth appears as a
straight and rising line when a logarithmic scale is used on the
y axis to represent cell number while time is represented on
the x axis on an arithmetic scale.
Extrapolation of this pattern of growth, which is typi-
cal of murine leukemias, led to the idea that roughly one
liter of tumor cells would represent a lethal volume of
cancer in humans and that diagnosis of the disease could
not be expected until somewhere between 1010 and 1011
tumor cells.
The concept of log kill is represented graphically in
Figure 1. Exponential increase in tumor cell number can be
interrupted by one or more cycles of treatment, each of
which produces a substantial fall in the log number of cells.
However, the effect of each treatment is simply to move the
exponential growth curve to the right, at which point the
rise in cell number resumes at its previous rate [5-9].

Correspondence: Larry Norton, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021-
6007, USA. Telephone: 212-639-6425; Fax: 212-717-3743; e-mail: nortonl@mskcc.org. Received February 6, 2001;
accepted for publication March 8, 2001. ©AlphaMed Press 1083-7159/2001/$5.00/0

The Oncologist 2001;6(suppl 3):30-35 www.TheOncologist.com

Norton 31

Exponential growth Concept of log kill

1012 1012

Death
109 109
Cell number

Cell number
106 Diagnosis 106
(recurrence)

103 103

Treatment
100 100
0 3 6 9 12 15 18 0 3 6 9 12 15 18
Weeks Weeks

Figure 1. Concept of log-cell kill: the effect of each treatment to move the exponential growth curve to the right.

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This relatively simple picture is complicated by hetero-
geneity in the sensitivity of tumor cells to a particular drug.
A resistant clone will not suffer a fall in cell number with
initial treatment and will continue to grow exponentially
[10]. This problem can be tackled by introducing a second
drug into therapy [5, 6, 9-11]. Figure 2 shows how this
might achieve a log kill of all cell populations. However, to
maintain this effect, the two-drug combination needs to be
continued for repeated cycles (Fig. 2). This concept forms
the rationale for combination chemotherapy.
The clinical situation, of course, is considerably more
complicated. Combining an agent which achieves a 50%
response rate (RR) as monotherapy with another agent
with a 50% RR achieves an RR of perhaps 60% or 65%,
rather than 100%, since cell populations overlap in drug
sensitivity [11].
CELL KILL AND ADJUVANT CHEMOTHERAPY
Figure 3 presents a series of curves taken from data pre-
sented recently at the overview meeting of the Early Breast
Cancer Trialists Collaborative Group in Oxford, England
[2]. The top left panel shows curves for overall survival and
relapse-free survival which are based on data pooled from
the control arms of all available studies of adjuvant
chemotherapy. The panel below shows a set of four growth
curves which can explain these results. On the left-hand
side is a curve showing the 90th percentile growth rate:
90% of tumors grow at a slower rate than that indicated by
this line. At the right is the 60th percentile growth rate.
The top right-hand panel shows the curves for relapse-free
and overall survival using data pooled from the chemotherapy
arms of all available studies. Below are the growth curves that
can account for these data. Compared with the curves gener-
ated from data from control patients, they are all shifted to the
right. In essence, they show that the improved relapse-free and
overall survival seen clinically in trials of adjuvant chemother-
apy could have been achieved through a one-log cell kill. This
ignores any effects on variables such as regrowth kinetics but
is important in showing that the basic concept of the log-kill
model is valid in the adjuvant setting.

Heterogeneity in drug sensitivity Combination chemotherapy

1012 1012
Resistant cell line

9
10 109
Cell number

Cell number

106 106

103 103

Treatment Treatment
100 100
0 3 6 9 12 15 18 0 3 6 9 12 15 18
Weeks Weeks

Figure 2. Combination chemotherapy is necessary to achieve log kill where populations of tumor cells are not equally sensitive to a single drug.
32 Cell Kill and Emerging Adjuvant Therapies

Figure 3. Cell kill explains

impact of adjuvant chemother- Control Chemotherapy
apy. Adapted with permission 100
from [2].
OS

Percent
75 OS
Importantly, the growth
curves that fit the data gener- 50 RFS
RFS
ated by trials of adjuvant ther-
apy are not the straight lines of 25
exponential growth. They curve
0
in the particular sigmoid shape
known as “Gompertzian” [5, 10,000
90th
Tumor size in CC
12-14]. Since the rate of cell 1,000 90th
growth is faster in the early 100
rather than the latter part of the
60th
10 60th

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curve, the effect of early inter-
vention is greater than that of 1
later intervention. The log kill is
therefore probably greater in 0.1
tumors of small volume than 0 5 10 15 0 5 10 15
in those of larger volume, and Years
this is reflected in Figure 4.
In this situation, administration of chemotherapy using
conventional alternating schedules will not eradicate cell
1012
clones of different sensitivity [15]. As cells sensitive to one
drug are being killed, resistant cells are growing; and the
109
same is true when the second drug is used (Fig. 5).
Cell number

In this situation, delays in drug administration or sched-

106
ules which cycle drugs over a more prolonged period may
actually work against the efficacy of treatment. An alterna-
103 tive is to compress the conventional schedule, giving doses
closer together in time in so-called “dose-dense” therapy [5,
100 15, 16]. In simulations, this simple manipulation achieves a
0 3 6 9 12 15
Weeks considerably greater efficacy by minimizing regrowth of
cells between cycles of treatment (Fig. 6).
This concept can be extended to encompass situations
Figure 4. Log kill in Gompertzian growth.
of heterogeneous drug sensitivity through the use of
sequential dose-dense regimens (Fig. 7) [5, 6, 17-19]. This
1012 represents a new view of the way to proceed. However,
there is empirical evidence to justify it, and the approach
underlies several important ongoing clinical trials involving
109
agents such as the taxanes.
Cell number

106
ONGOING CLINICAL TRIALS
In the Cancer and Leukemia Group B (CALGB) 9344
103
study, patients with T1-3 N1-2 breast cancer were randomized
to receive a fixed dose of 600 mg/m2 cyclophosphamide plus
100
0 3 6 9 12 15 doxorubicin at either 60, 75, or 90 mg/m2 for four cycles [20,
Weeks 21]. This was followed by a second randomization to either
four doses of 175 mg/m2 paclitaxel or no further chemo-
Figure 5. Alternating therapy and the effect on log-cell kill in therapy, with tamoxifen administered in hormone receptor-
Gompertzian growth. positive disease. The dose of doxorubicin given had no impact
Norton 33

Conventional schedule Dose-dense therapy

1012 1012

109 109
Cell number

Cell number
106 106

103
103

100
0 3 6 9 12 15 100
0 3 6 9 12 15
Weeks
Weeks

Figure 6. Effect of dose-dense therapy on log-cell kill in Gompertzian growth.

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paclitaxel and cyclophosphamide in two- or three-week
1012
cycles.
Several trials are also investigating the effects of combi-
109 nation chemotherapy in a more formal way. A Breast Cancer
Cell number

International Research Group (BCIRG) trial is randomizing

106
patients to six cycles consisting of either docetaxel 75 mg/m2
or 500 mg/m2 5-fluorouracil (5-FU), with each drug combined
with doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2
103
(i.e., TAC versus FAC). An American Intergroup study is
investigating a similar comparison between 60 mg/m2 each
100 of doxorubicin and docetaxel versus 60 mg/m2 doxorubicin
0 3 6 9 12 15
Weeks plus 600 mg/m2 cyclophosphamide, each administered for
four cycles.
Figure 7. Sequential dose-dense therapy.
The choice between taxanes and schedules is being inves-
tigated in an Intergroup/Eastern Cooperative Oncology Group
study in which node-positive, HER-2 negative patients are ran-
on survival. However, the intriguing aspect of the study is seen domized to one of four treatment arms. Following four cycles
when its results are set in the context of data presented from of doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2,
other trials at the recent Oxford meeting [20-22]. patients receive either four cycles of 175 mg/m2 paclitaxel
Table 1 shows that single-agent adjuvant chemotherapy
has a weak and non-significant impact on the odds of recur-
rence and death. However, combination chemotherapy using Table 1. Impact of prolonged adjuvant chemotherapy on the annual odds of
CMF has a large and significant effect, while epirubicin plus recurrence and death [20-22]
doxorubicin further increases the annual odds of survival by
Comparison % Reduction (± SD) in annual odds of
approaching 16%. The sequential use of doxorubicin plus
cyclophosphamide (AC) followed by paclitaxel improved Recurrence Death
the odds of recurrence-free and overall survival by greater Single agent versus Not (3932)* +7.9 ± 4.8 +0.7 ± 4.7
than 20% when compared with AC alone. CMF versus Not (12175)* +23.0 ± 3.0 +15.0 ± 3.0
Since this trial, the CALGB has attempted to further Dox/Epi versus CMF (13756)* +10.8 ± 3.1 +15.7 ± 3.4
explore the possibilities of clinical benefit by comparing >6 months versus ≤6 months (3611)* +7.0 ± 5.0 +7.0 ± 6.0
a three-weekly regimen of AC followed by paclitaxel AC→T versus AC (3121)** +22 ± 6 +25 ± 8
with a two-weekly, and hence, more dose-dense regimen
Abbreviations: AC = doxorubicin plus cyclophosphamide; T = paclitaxel;
using the same drugs with G-CSF support. In this Dox/Epi = doxorubicin/epirubicin
Intergroup/CALGB 9741 study, patients are also being **Early Breast Cancer Trialists Collaborative Group, Oxford, 9/00
randomized to two arms of the study in which the three **CALGB 9344, U.S. Food & Drug Administration Hearing, 9/99
drugs are given sequentially as doxorubicin followed by
34
q 3 weeks, 10 cycles of weekly 80 mg/m2 paclitaxel, four
cycles of docetaxel 100 mg/m2 q 3 weeks, or 10 cycles of
weekly docetaxel 35 mg/m2. The weekly schedules are dose-
dense. However, only randomized trials such as this can
determine whether they are more effective.
In the National Surgical Adjuvant Breast and Bowel
Project (NSABP) B-27 trial, patients with T1-3 disease are
being randomized to three arms following an initial four
cycles of doxorubicin 60 mg/m2 plus cyclophosphamide
600 mg/m2. In one arm, patients are treated with surgery
alone; in a second arm, surgery is preceded by four cycles
of docetaxel 100 mg/m2; and in the third arm, four cycles
of docetaxel 100 mg/m2 chemotherapy follow surgery.
The NSABP B-30 trial represents a head-to-head com-
parison between sequential and combination chemother-
apy. Patients will receive either doxorubicin 60 mg/m2
plus cyclophosphamide 600 mg/m2 (AC) followed by four
courses of docetaxel 100 mg/m2, AC alone, or AC com-
bined with docetaxel 60 mg/m2. Dose modification is fre-
quently needed to achieve combination chemotherapy, and
such modification may decrease efficacy. The trial there-
fore represents an important attempt to establish which
approach to therapy is optimal. The BCIRG 005 study also
addresses the question of dose as well as combination
chemotherapy. In this trial, patients who are node positive
and HER-2 negative on the fluorescence in situ hybridiza-
tion assay will receive either four cycles of AC followed by
four of docetaxel 100 mg/m2 or six cycles of TAC.
In an Italian multicenter trial, patients with stage II dis-
ease and three or more positive lymph nodes are being ran-
domized to treatment with epirubicin followed by docetaxel
followed by CMF or to epirubicin followed by docetaxel
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