Computer Program to Assist in Making Decisions About
Adjuvant Therapy for Women With Early Breast Cancer
By Peter M. Ravdin, Laura A. Siminoff, Greg J. Davis, Mary Beth Mercer, Joan Hewlett, Nancy Gerson, and Helen L. Parker
Purpose: The goal of the computer program Adju-
vant! is to allow health professionals and their patients
with early breast cancer to make more informed deci-
sions about adjuvant therapy.
Methods: Actuarial analysis was used to project out-
comes of patients with and without adjuvant therapy
based on estimates of prognosis largely derived from
Surveillance, Epidemiology, and End-Results data and
estimates of the efficacy of adjuvant therapy based on
the 1998 overviews of randomized trials of adjuvant
therapy. These estimates can be refined using the Prog-
nostic Factor Impact Calculator, which uses a Bayesian
method to make adjustments based on relative risks
conferred and prevalence of positive test results.
Results: From the entries of patient information
(age, menopausal status, comorbidity estimate) and
tumor staging and characteristics (tumor size, number
of positive axillary nodes, estrogen receptor status),
baseline prognostic estimates are made. Estimates for
the efficacy of endocrine therapy (5 years of tamoxifen)
HE PRACTICE OF medicine has been moving toward
T more evidence-based and quantitative formats. This
trend has been occurring during an era in which there are
increasing data concerning the efficacy and safety of ther-
apies from clinical trials. A growing number of tools have
been developed that produce numerical estimates of the
probability of outcomes, such as the Gale model, which
produces estimates of the risk of developing breast cancer in
individual women in the general population.1 Somewhat
paradoxically, these numerical tools have the potential to
humanize medicine; for example, if the results are shared
with the patient in a comprehensible format, the patient can
become an informed partner in making decisions about
different therapeutic options.
These tools have great potential in making treatment
decisions in the adjuvant therapy for individual patients
From the University of Texas Health Sciences Center, San Antonio,
TX, and Case Western Reserve, Cleveland, OH.
Submitted May 18, 2000; accepted September 22, 2000.
Supported in part by grant no. RO1-HSO8516 from the National
Cancer Institute.
Address reprint requests to Peter M. Ravdin, MD, PhD, Division of
Oncology, University of Texas Health Sciences Center at San Antonio,
7703 Floyd Curl Dr, San Antonio, TX 78284; email: pravdin@
swog.org.
© 2001 by American Society of Clinical Oncology.
0732-183X/01/1904-980
980 Journal of Clinical Oncology, Vol 19, No 4 (February 15), 2001: pp 980-991
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
and of polychemotherapy (cyclophosphamide/metho-
trexate/fluorouracil–like regimens, or anthracycline-
based therapy, or therapy based on both an anthracy-
cline and a taxane) can then be used to project
outcomes presented in both numerical and graphical
formats. Outcomes for overall survival and disease-
free survival and the improvement seen in clinical trials,
are reasonably modeled by Adjuvant!, although an
ideal validation for all patient subsets with all treat-
ment options is not possible. Additional speculative
estimates of years of remaining life expectancy and
long-term survival curves can also be produced. Help
files supply general information about breast cancer.
The program’s Internet links supply national treatment
guidelines, cooperative group trial options, and other
related information.
Conclusion: The computer program Adjuvant! can
play practical and educational roles in clinical settings.
J Clin Oncol 19:980-991. © 2001 by American
Society of Clinical Oncology.
with early breast cancer. Breast cancer adjuvant therapy is
an important area for advancing techniques of evidence-
based treatment decision making for several reasons. First,
there are often several reasonable therapeutic options avail-
able. Specifically, in this clinical situation, the decision can
often be between options of no additional therapy, chemo-
therapy, hormonal therapy, or chemoendocrine therapy.
There are also options concerning the choice of the specific
type of chemotherapy. Second, the degree of benefit in
terms of disease-free survival (DFS) and overall survival
(OS) can be small and uncertain enough to make the
decision as to whether to receive a given option something
for which individual patients might express very different
preferences. Studies have shown that many patients are not
given quantitative information about their prognoses with
and without adjuvant therapy and often make inaccurate
estimates.2,3 Without such information as a point of refer-
ence, these patients are not adequately informed partners in
deciding whether and what type of adjuvant therapy might
be most appropriate. Furthermore, the oncologists often are
uncertain about what quantitative prognostic estimates to
apply to any given patient.4
To address this problem, we developed a decision aid—a
simple-to-use computer program entitled Adjuvant!. This
program is designed to produce prognostic estimates of
outcome with and without therapy, based on the estimates of
individual patient prognosis and the efficacy of different
TOOL FOR ADJUVANT THERAPY DECISION MAKING
adjuvant therapy options. The computer program presents
this information on the computer screen for the physician as
well as printed pages for use with patients. This article
describes the program in detail. The use and impact of this tool
in real-time treatment decision-making encounters with stages
I to III breast cancer patients is currently being investigated.
METHODS
The program Adjuvant! version 2.2 runs in the Windows 95, 98, and
NT environments. It requires a 32-bit 486 or higher processor. It is
self-installing and requires 1.5 megabytes of hard drive space. Output
requires a printer, and we recommend a color printer. Guidelines,
cooperative group clinical trial information, literature search engines,
and websites for patient information materials can be accessed from
Adjuvant! if there is an Internet connection.
The fundamental purpose of Adjuvant! is to supply estimates of the
net benefit to be expected for systemic adjuvant therapy for individual
breast cancer patients. These estimates of benefit are obtained by
estimating the reduction of risk of negative outcomes for individual
patients. This is done by estimating a patient’s risk of negative outcome
(death or relapse) and then multiplying that by the proportion of
negative events that a given adjuvant therapy is known to prevent.
Estimates of prognosis are based mainly from the Surveillance,
Epidemiology, and End-Results (SEER) registry estimates of outcome
for breast cancer patients in the general population in the United States.
Estimates of the efficacy of therapy are based mainly on the propor-
tional risk reductions (PRR) that can be obtained from the 1998
Overview summaries of the effectiveness of adjuvant therapy based on
data from nearly all randomized clinical trials.5,6
A simplified view of how this is done is easy to understand. For
example, consider an individual patient who, because of tumor size and
number of nodes, has a 60% risk of dying of breast cancer at the
10-year follow-up. This patient can be given an adjuvant therapy that
can achieve a PRR of 25%. This should reduce her breast cancer
mortality by 60% times 25%, which equals 15%. A subtle but
important point is that the Overview PRR are for effects of the therapy
in the annual risk of negative outcome. For a patient with a 60% risk
of death at 10 years, the average annual risk of breast cancer–related
death is 8.8%. Therefore, the expected survival would be 91.2% of the
preceding year. This would result in survivals of 91.2%, 83.3%, 76.0%,
69.3%, 63.2%, 57.7%, 52.7%, 48.0%, 43.8%, and 40%, for years 1 to
10, respectively. However, after an adjuvant therapy affording a PRR
of 25%, the annual risk of breast cancer–related death would be 6.6%
(8.8% reduced by 25%). This would result in survivals of 93.4%,
87.3%, 81.6%, 76.2%, 71.2%, 66.5%, 62.2%, 58.1%, 54.3%, and
50.7% for years 1 to 10, respectively. The expected benefit would not
be 15% but only 10.7%. A second consideration that can reduce further the
impact of adjuvant therapy is competing non– breast cancer– expected
natural mortality. Obviously, if a high percentage of patients were
expected to die of non– breast cancer–related causes, then there would be
fewer patients that might obtain the net benefit of adjuvant therapy.
Adjuvant! takes these effects into account by using an actuarial life
table technique for calculating survival.7 At the time of diagnosis (year
0), it starts with a survival probability of 100%. Then the survival
probability 1 year later is calculated as 100% minus the percentage of
patients that die over a year’s time of natural causes (for women of the
patient’s age taken from United States mortality statistics) and also
minus the percentage of patients expected to die over a year’s time of
breast cancer. This process is calculated iteratively year by year with
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981
the probability of survival being calculated in each succeeding year. Of
course, year-by-year the percentage risk of natural mortality gradually
increases (as the patient grows older), and the year-by-year risk of
dying of breast cancer (after a more complex pattern) eventually begins
to decrease. In addition, estimates of the effectiveness of adjuvant
therapy can be used to change the year-by-year estimates for breast
cancer–specific mortality. Together this methodology can allow one to
estimate the relative contributions of natural and breast cancer–specific
mortality to the overall mortality of given patients in scenarios where
they receive adjuvant therapy and where they do not.
Estimates of Prognosis
The estimate of risk of breast cancer–related death at a 10-year
follow-up is supplied by Adjuvant! based on the tumor size, the number
of involved nodes, and to a minor extent, estrogen receptor (ER) status.
These estimates are based on an analysis of data from the SEER tumor
registry database, which follows approximately 10% of all breast
cancer cases in the United States, as well as information from a number
of sources including the Overview meta-analyses.5,6 The primary data
used in this analysis were individual demographic, staging, and
outcome information from the SEER-9 Public Registries Files from
August 1998, as provided on the April 1999 SEER*Stat2 Version 2.0
CD ROM. Patients included in the initial analyses were women who
had invasive, unilateral, noninflammatory disease, had undergone
definitive surgery (with radiation if lumpectomy), and had axillary
staging with at least six nodes sampled. For inclusion in the analysis,
patients must have had a known tumor size, number of nodes sampled,
and number of nodes positive for tumor.
There are some limitations of the SEER registry-derived data. SEER
registry-defined information has vital status during follow-up but does
not have information about the type of adjuvant therapy received,
relapse status, or reliable cause of death information. Thus, only
survival analyses can be done from SEER data. Estimates of breast
cancer–related mortality made using SEER data must be derived
indirectly from total survival after adjustment for expected age-
adjusted natural mortality. This analysis was done using the
SEER*Stat2 software.
As a first part of this analysis, the effect of age on breast cancer–
related mortality at 5 years was examined. The results for this analysis
for patients with small node-negative tumors (tumor size 0.1 to 1.0 cm),
average node-negative tumors (tumor size 2.1 to 5.0 cm), and interme-
diate risk node-positive tumors (one to three positive nodes and tumor
size 2.1 to 5.0 cm) are shown in Fig 1. This analysis shows that young
patients (in their 20s and 30s) seem to have a worse prognosis overall,
and that patients in their 70s and 80s have a comparatively good
prognosis. The method of deriving breast cancer mortality by adjust-
ment of total mortality for expected natural mortality gives nonsensical
negative breast cancer–specific mortalities for older patients with small
node-negative tumors. A reasonable explanation for this effect is that
older patients (in their late 60s, 70s, and 80s) who have the type of
medical access that allows the discovery of such early tumors and who
get definitive treatment are healthier and overall have less natural
mortality than might be expected for their age. To eliminate this source
of bias, and considering that women younger than 35 seem to have
stage by stage a somewhat worse prognosis than older women, the
analyses done for assigning stage-related prognoses were restricted to
women in the SEER registry from 35 to 59 years of age.
The SEER data were then used to calculate the breast cancer–related
mortality for patients at the 5-year follow-up and to extrapolate breast
cancer mortality at the 10-year follow-up. Such extrapolations were
necessary because presently the available SEER data have only
982 RAVDIN ET AL

Fig 1. Effects of age on esti-

mates of breast cancer–specific
mortality.

complete tumor size and number of nodes for the last 9 years of data
collection and ER status information for the last 7 years. The results of
the analysis for 5 years of follow-up can be seen in Table 1. An
unexpected aspect of this analysis is that ER status seems to be a strong
prognostic factor, which is inconsistent with the literature, which
suggests that ER status is not strongly prognostic. This discrepancy can
be explained in part by the short follow-up. The annual hazard rates for
patients when considering ER can be seen in Fig 2. Clearly, the time
dependence of the hazard is markedly different for ER-negative and
ER-positive tumors. Patients with ER-negative tumors annual risk of
mortality peaks in the first 5 years, and patients with ER-positive
tumors have a peak hazard that occurs later.
Using SEER data, annual hazard estimates derived from the 1998
Overviews5,6 and other sources,8,9 it was estimated that for ER-positive
cases, the average annual hazard rates in the first 5 years were half that
of the average rates for years 6 through 10; for ER-negative cases, the
average annual hazard rates in the first 5 years were twice that for years
6 through 10. Using these approximations, extrapolated estimates of the
breast cancer–specific mortality rates at the 10-year follow-up could be
made for ER-positive and ER-negative cases. Again, particularly for
node-negative cases, ER status was a prognostic variable but to a lesser
degree (Table 2). Extrapolations of breast cancer–specific mortality at
10 years of follow-up were also made for all cases (regardless of ER
status) by using the average observed annual hazard rates in years 6, 7,
and 8 as that for years 9 and 10, and then using these hazard rates to
extrapolate the cumulative breast cancer–specific mortality at 10 years’
follow-up. The extrapolated 10-year breast cancer–specific mortality
rates derived from cases regardless of ER status for low-risk tumors lay
between those of ER-positive and negative cases, but for high-risk
tumors, this was not the case. This is might occur either because cases
without ER status had some special feature (approximately 25% of the
cases had no reported ER), or because the extrapolations for the
ER-positive and -negative subsets were in error.
These uncertainties for the cases with defined ER together with the
fact that estimates for cases irrespective of ER were based on more
cases with longer follow-up, led to the decision to base the estimates of
breast cancer–specific mortality on all cases irrespective of ER.
Adjustments for slightly better and worse outcomes for ER-positive
and ER-negative cases, respectively, were made by adjusting ER
undefined estimates using a modest 1.3 relative risk, which large
long-term studies have suggested are appropriate in untreated node-
negative patients.10,11
The SEER estimates of stage-specific mortality are influenced by the
fact that many of the patients received adjuvant systemic therapies.
This adjustment was made by modifying the estimates (increasing) for
the impact of adjuvant therapy that improved the outcome of stage 1
cases (in which many patients would not have received adjuvant
chemotherapy) by a proportional 15%, and by a proportional 30% for

Table 1. Observed Excess Mortality in Breast Cancer Patients*

All Cases ER Positive ER Negative

Mortality SE Mortality SE Mortality SE

Group No. (%) (%) No. (%) (%) No. (%) (%)

Node negative
T1, 0.1-2.0 cm 18,995 2.8 0.4 9,176 1.3 0.6 3,315 5.4 1.4
T2, 2.1-5.0 cm 6,232 10.9 1.1 2,358 6.4 1.7 1,721 17.6 2.8
1-3 positive nodes
T1, 0.1-2.0 cm 4,570 8.4 1.2 2,250 5.7 1.7 795 17.1 4.3
T2, 2.1-5.0 cm 3,715 19.2 1.8 1,661 14.3 2.8 842 29.4 4.6
4-9 positive nodes
T1, 0.1-2.0 cm 1,303 18.2 2.9 605 13.7 4.4 240 29.3 9.0
T2, 2.1-5.0 cm 1,795 28.3 2.8 815 18.4 3.9 379 38.9 7.3
ⱖ 10 positive nodes
T1, 0.1-2.0 cm 493 38.0 5.7 222 41.2 10.0 100 47.1 15.9
T2, 2.1-5.0 cm 865 39.3 4.3 350 32.3 7.2 197 54.6 11.0

*SEER registry at 5 years (in %) after correction for expected competing (nonbreast cancer) sources of mortality.

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TOOL FOR ADJUVANT THERAPY DECISION MAKING 983

Fig 2. Effects of ER on annual

hazard rates of breast cancer–spe-
cific mortality. ER status: ⽧, ER
negative; ● , ER positive; f , ER
undefined.

stages II and III cancers. Estimates of breast cancer–specific mortality
at 10 years of outcome for untreated patients (Table 2) were derived by
this method. Such adjustments may introduce small systematic errors
into the estimates. For example, for patients with stage 1 breast cancer,
considering the average estimate of PRR provided by adjuvant therapy
of approximately 30% (Table 3) and the estimate that approximately
half of the patients receive such therapy, the adjustment of 15% was
made. The true adjustment might be somewhere between 0% (if no
patients receive a systemic adjuvant therapy) and 30% (when all
patients receive adjuvant therapy). Thus, a systematic relative error of
15% may have been introduced, which is modest.
SEER does not collect data on relapse, and there are no large
population-based sources of relapse data. Relapse estimates were
derived from the mortality estimates by noting that breast cancer–
specific relapse rates (defined as any recurrence (distant, regional, or
contralateral) must be slightly higher than mortality rates because there
are always some patients who have relapsed but not yet died. Also,
there are some types of relapse (for example, contralateral) that are not
usually associated with eventual mortality. Considering that on aver-
age, mortality occurs approximately 3 years after relapse and that the
annual hazard of contralateral breast cancer is approximatley 0.65%,
the annual hazard of relapse is estimated as 1.3 times the breast cancer
mortality hazard plus 0.65%. This formula was used to convert
estimates of 10-year cumulative hazard of mortality to the 10-year
cumulative hazard of relapse. The estimates of breast cancer–specific
mortality and breast cancer relapse or recurrence used by Adjuvant! are
presented in Table 3.
Derivation of Estimates of the Efficacy of
Adjuvant Therapy
The estimates of PRR used by Adjuvant! either are taken directly
from the 1998 Overviews5,6 of adjuvant therapy of early breast cancer
or were derived indirectly from these estimates. The PRR for the 1998
Overview estimates were for recurrence and death.
The definition of recurrence used in the Overviews5,6 was first
reappearance of breast cancer at any site (local, contralateral, or
distant), and deaths due to breast cancer (if breast cancer had not been
documented). Deaths because of unknown causes were included as
breast cancer–related deaths. Deaths due to non– breast cancer–related
events were not included as recurrence events, but patients were
censored at that time. A careful definition of recurrence is important
because such a wide variety of definitions are used in different trials,

Table 2. Evolution of Estimates of Rates of Breast Cancer Mortality at 10 Years’ Follow-Up*†

With Additional Adjustment for Effects of

Extrapolated from SEER Data With Assumed ER Impact 1.3 RR Adjuvant Therapy

Group ERP ERN All ERP ERN All ERP ERN All

Node negative
T1, 0.1-2.0 cm 3.8 8.0 6.6 6.0 7.8 6.6 7 9.1 7.7
T2, 2.1-5.0 cm 18.0 25.1 20.8 19.1 24.2 20.8 26.3 33.0 28.6
1-3 positive nodes
T1, 0.1-2.0 cm 16.2 24.4 20.7 19.0 24.1 20.7 26.2 32.8 28.4
T2, 2.1-5.0 cm 37.4 40.5 34.9 32.2 40.0 34.9 43.2 52.7 46.5
4-9 positive nodes
T1, 0.1-2.0 cm 36.0 40.4 36.7 33.9 42.0 36.7 45.3 55.0 48.7
T2, 2.1-5.0 cm 46.2 51.9 43.5 40.3 49.4 43.5 53.0 63.4 56.7
ⱖ 10 positive nodes
T1, 0.1-2.0 cm 80.9 61.2 58.5 54.7 65.3 58.5 69.1 79.6 73.0
T2, 2.1-5.0 cm 70.0 68.9 64.6 60.7 71.4 64.6 75.2 85.1 79.0

Abbreviations: ERP, estrogen receptor positive; ERN, estrogen receptor negative.

*This was a simple extrapolation, assuming a relative risk of 1.3 conferred by ER status, and adjusting for the impact of adjuvant therapy.
†For patients from 35 to 59 years of age.

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984 RAVDIN ET AL

Table 3. Risk of Breast Cancer–Specific Mortality and Estimates of Breast derived as the product of the PRR for polychemotherapy and tamox-
Cancer Recurrence (distant, local, or contralateral) at 10 Years Follow-Up ifen. The actual equation used is:
Breast Cancer–Specific Breast Cancer Relapse
PRR chemoendocrine therapy ⫽ 1 ⫺ 关共1 ⫺ PRR chemotherapy兲
Mortality Derived from Rates Derived from
SEER Data (%) Mortality Rates (%) ⫻ 共1 ⫺ PRR tamoxifen兲兴 . (1)
Group All ERP ERN ERP ERN All
For example, in premenopausal women with ER-positive tumors, the
Node negative PRR for mortality given by the 1998 Overviews are 20% and 28% for
T1a, 0.1-0.5 cm 3 3 3 10 10 10 polychemotherapy and tamoxifen, respectively. The indirectly inferred
T1b, 0.6-1.0 cm 4 4 5 11 11 12 PRR for chemoendocrine therapy is 100 ⫺ (80%) ⫻ (72%) ⫽ 42%.
T1c, 1.1-2.0 cm 11 10 12 19 18 21 The 1998 Overview5 of polychemotherapy trials reports results that
T ⫽ 2.1-3.0 cm 27 25 31 37 35 42 are largely dominated by trials with cyclophosphamide/methotrexate/
T ⫽ 3.1-4.0 cm 32 29 37 43 40 48 fluorouracil (CMF)–like regimens. The Overview5 also reports that
T ⫽ 4.1-5.0 cm 34 31 39 45 42 50 anthracycline-based regimens deliver approximately 11% more PRR
1-3 positive nodes for recurrence and mortality compared with non–anthracycline-based
T1, 0.1-2.0 cm 28 26 33 39 36 44 regimens. The Overview does not present a separate analysis of the
T2, 2.1-5.0 cm 46 43 53 58 55 64 PRR afforded by anthracycline-based regimens versus no polychemo-
4-9 positive nodes therapy, so this must again be indirectly inferred. This is performed
T1, 0.1-2.0 cm 49 45 55 60 57 67 using the above equation. This same problem is addressed when
T2, 2.1-5.0 cm 57 53 63 68 65 75 including the impact of adjuvant taxanes. Here the results are depen-
ⱖ 10 positive nodes dent on the short-term follow-up of one trial, which was not included
T1, 0.1-2.0 cm 73 69 80 83 80 89 in the 1998 Overviews (as the user is reminded by Adjuvant! if they
T2, 2.1-5.0 cm 79 75 85 88 85 93 choose adjuvant therapy that includes a taxane). Because the estimates
of PRR at less than 5 years are generally much more optimistic than
seen at 10 years of follow-up, the impact on PRR for mortality and
sometimes including non– breast cancer–related deaths and second recurrence is estimated to be 11%, not the 22% reported in the early
primary cancers. analysis of that trial.
The definition of death used in the Overviews was death due to any Adjuvant! provides estimates of PRR for recurrence and breast
cause. This definition is not ideal inasmuch as it mixes both breast cancer–related mortality. These estimates are selected based on meno-
cancer–related and nonrelated causes of death. This is not the definition pausal status, ER status, and the type of chemotherapy selected
used by Adjuvant!. Adjuvant! presents the user with PRR for breast (CMF-like, including an anthracycline or both anthracycline and
cancer–specific mortality. The justification for this is as follows: taxane). The estimates are listed in Table 4. The user of Adjuvant! is
Expected non– breast cancer death rates at 10 years’ follow-up for not constrained to use the estimates provided but can directly enter
women in good health are approximately 1%, 2%, 6%, 12%, and 24% estimates of efficacy for individual patients or entire sets of estimates
in their 30s, 40s, 50s, 60s, and 70s, respectively.12 Most estimates of that can be saved for later use.
efficacy of adjuvant therapy are derived by the Overviews5,6 from the
outcomes of women younger than 70 and scenarios in which the rate of
RESULTS
breast cancer–related death is much greater than that of non– breast The program that we have developed, Adjuvant!, begins
cancer–related death. Thus, these estimates can be used as a reflection
with a statement about its purpose, limitations, and a
of the PRR of breast cancer–related mortality without modification, as
performed by Adjuvant!. However, PRR given by the Overview for suggestion that it be used by health professionals and not
women 70 and older might be expected to be low because the majority directly by patients themselves, because of the importance
of deaths would be expected to be non– breast cancer related. Analyses of accurate information entry from sources such as pathol-
reported in the 1998 Overviews5,6 showed adjuvant therapies do not ogy reports. After acknowledging these statements, a sec-
have a significant effect on non– breast cancer–related mortality.
ond screen opens stating that the program makes estimates
Perhaps the lack of benefit on overall mortality (in terms of PRR) of
chemotherapy in women 70 and older is partially because a substantial for women with invasive breast cancers that are unicentric,
percentage of these deaths would be expected to be non– breast unilateral, and for whom special considerations must be
cancer–related and might obscure an effect on breast cancer–related made using the “help section” if the tumor is a special
mortality. Adjuvant! uses the PRR of average women 50 to 69 years of histology subtype (pure tubular, pure papillary, or pure
age for women 70 and older, but informs the user of the controversial
mucinous) or an inflammatory breast cancer. It states that
nature of this choice if an age of 70 or older is selected for the patient.
The 1998 Overviews5,6 report direct comparisons as made in the program makes estimates of outcome for patients after
randomized trials but do not make indirect comparisons that might be definitive tumor resection and axillary node dissection but
inferred. Thus, PRR are given in the 1998 Overviews5,6 for effective- before any systemic adjuvant therapy (neoadjuvant thera-
ness of adding tamoxifen or polychemotherapy, but they are not given py). Furthermore, patients must not have known residual or
for comparisons of no therapy versus combined therapy with both
metastatic disease. For patients receiving breast-conserving
chemotherapy and tamoxifen. Indirectly, such estimates can be inferred
because the 1998 Overviews suggest that the benefit of adjuvant surgery, there is an assumption that radiation therapy is
chemotherapy or tamoxifen occurs independently of whether the other planned. After these requirements are acknowledged, the
modality is used. Thus, the PRR for chemoendocrine therapy are program opens to the main screen.

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TOOL FOR ADJUVANT THERAPY DECISION MAKING 985

Table 4. Estimates of PRR Caused by Adjuvant Therapy

PRR for Breast Cancer–Specific Mortality (%) PRR for Breast Cancer Recurrence (%)

Combined Combined
Group/Therapy Tamoxifen Chemotherapy Chemoendocrine Tamoxifen Chemotherapy Chemoendocrine

Premenopausal patients
CMF-like 28/21/0* 20/23/35 42/39/35 50/37/0 29/33/37 65/58/37
Anthracycline-based 28/21/0 29/31/42 49/46/42 50/37/0 37/40/44 68/62/44
With both an anthracycline 28/21/0 37/39/49 54/52/49 50/37/0 44/47/50 72/67/50
and a taxane
Postmenopausal patients
CMF-like 28/21/0 9/11/17 34/30/17 50/37/0 15/22/29 57/51/29
Anthracycline-based 28/21/0 19/21/26 42/37/26 50/37/0 24/31/37 62/56/37
With both an anthracycline 28/21/0 28/30/34 48/44/34 50/37/0 33/38/44 66/61/44
and a taxane

*As used by Adjuvant! for ER-positive/, ER-undefined/, and ER-negative patients.

The main screen (Fig 3) has four major components: (1)
a section that allows patient information to be entered and
provides an estimate of the risk at 10 years’ follow-up of
breast cancer–related death or relapse unconfounded by
therapy or competing causes of morbidity or mortality; (2)
a section that provides efficacy information (in terms of
PRR) for different adjuvant therapy options; (3) a section
that shows the resulting projections of outcome in numerical
and graphical format; and (4) a tool bar that allows the user
to save patient information, print results, and access the
program’s help files.
Entering Patient Information
The major parameters used for adjuvant therapy decision
making must be entered into the program’s Patient Infor-
mation section. The Age is the chronologic age (in years) of
the patient. This information is used by the program to
calculate the expected natural mortality. Also, it is used to
Fig 3. Main screen for Adjuvant!
produce the default estimate of menopausal status. Meno-
pausal Status is (by default) assigned as postmenopausal for
women ⱖ 50 years old but can be overridden. This
information effects estimates of the effectiveness of adju-
vant chemotherapy. Comorbidity is an estimate of the
general health of the individual for whom the estimates are
being made—the default is Minor Problems. The possible
choices are Perfect Health, Minor Problems, Average for
Age, Major Problems (⫹10), Major Problems (⫹20), and
Major Problems (⫹30). There are a broad range of estimates
because the chronologic age clearly does not define natural
mortality rates if comorbidity is not considered. The age-
specific mortality rates for average women in the United
States population12 (in Adjuvant! as Average for Age) are
an overestimate for most women. Much of the mortality at
any given age is driven by preexisting health problems.
Therefore, most women have natural mortality rates that are
predictably better than those for the general population.
Adjustment for lack of comorbidity is because the actuaries
have recognized (but not precisely defined) a population of
select patients who have no comorbidity and who have
lower short-term mortality rates.13,14 In older women, this
may be only one third of the age-adjusted average initially
but rises to the average within approximately 10 to 15 years.
This select population’s natural mortality estimates are
provided by selecting Perfect Health. Adjuvant! selects the
default Minor Problems, which is the average of Perfect
Health and Average for Age.
ER Status is used by the program as a crucial parameter
in determining the efficacy of systemic adjuvant therapy
options and in a minor role, in determining prognosis.
Although Undefined is the default, it is anticipated that
essentially all patients will have a defined ER status. ER
status should be entered as either positive or negative by any
criteria used by the laboratory making the measurement.

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986 RAVDIN ET AL

PGR (progesterone receptor) status does not influence the

entry if the patient is ER-positive. There is some uncertainty
as to whether PGR status should influence what is entered if
the patient is in the unusual situation of being ER-negative
but PGR-positive (only approximately 5% of breast cancer
patients are in this category). The efficacy of adjuvant
therapy in the subset of patients who are ER-negative but
PGR-positive is not well defined, but based on the efficacy
of endocrine therapy in patients with metastatic disease with
this receptor status, it is probable that these patients behave
like ER-positive patients. Therefore, the program suggests
that such patients be entered as ER-positive.
Tumor size is the greatest diameter of the tumor mea-
sured in centimeters. Frequently, there are several special Fig 4. Example of the PFIC refining the 10-year mortality estimate of 10%
issues that come up. One is whether, in a tumor with both for the impact of a prognostic factor that confers a relative risk of 2 and with
a prevalence of high-risk results of 20% (similar to Her2 amplification by
intraductal and invasive components, the tumor size used in
fluorescence in situ hybridization by some methodologies).
estimates should be that of the entire tumor or that of the
invasive component. The data from the SEER registry are
based on the size of the invasive component. Because the
prognostic estimates made by Adjuvant! are based primarily 10-Year Risk Box or using a calculator (the icon to the left
on SEER data, the size of the invasive component of the of the 10-Year Risk).
tumor should be entered. Positive Nodes are the total The Prognostic Factor Impact Calculator (PFIC) uses a
number of positive axillary nodes reported from the axillary Bayesian approach to adjust a prior prognostic estimate with
dissection (usually levels I and II). Number of positive information from a patient’s prognostic factor test if the
nodes, together with tumor size, are the major factors used prevalence of a positive test and the relative risk conferred
to make estimates of patient prognosis. If the patient has had is known. Using this calculator, the independent relative
a sentinel node biopsy, it is assumed that such a biopsy was risk (of tumor size and number of nodes) conferred, the
done by an experienced surgical team with a low false- prevalence of a positive test result (suggesting an unfavor-
negative rate.15 If, under these circumstances, the node was able prognosis), and the baseline prior-risk estimate are
negative, then enter 0. If the node was positive, then an entered. The calculator then produces 10-year prognostic
estimate of number of nodes cannot be made unless there estimates of outcome for patients with a favorable or an
was an axillary node dissection. An issue in the evaluation unfavorable prognostic test. This is done using the follow-
of nodal status is the prognostic significance of aggregates ing formulas:
of cancer cells within the lymph nodes missed on initial
sectioning but identified later on resectioning or with special Mortality Risk 共 low-risk group 兲 ⫽
immunochemical stains. It seems that discovery of nodal
共Average Risk for entire group兲/
involvement on standard histopathologic review does imply
that the patient has a worse prognosis,16,17 although this is 共关 % Patients in low-risk group兲 ⫹
less clear for such nodal metastases identified by immuno-
histochemical18 –20 or molecular biologic techniques.21 If 关% Patients in high-risk gruop ⫻ Relative Risk兴兲 (2)
the patient has undergone neoadjuvant therapy, then the
Mortality Risk 共 high-risk group 兲 ⫽
axilla nodal status may have been significantly downstaged
so that Adjuvant! cannot produce an estimate of prognosis 共Mortality Risk for low-risk group兲 ⫻ 共Relative Risk兲 (3)
and should not be used to make prognostic estimates.
An example of the use of PFIC can be seen in Fig 4.
The category 10-Year Risk is provided by Adjuvant!
based on the tumor size, the number of involved nodes, and
Efficacy of Adjuvant Therapy
ER status. It is largely derived from data from the SEER
tumor registry database22 as detailed in Methods. These These estimates come directly from the 1998 Over-
estimates can be accepted or modified based on additional views,5,6 were indirectly derived from them or, in the case
prognostic information. This can be done by directly enter- of the estimates of efficacy of adjuvant chemotherapy based
ing a prognostic estimate from a literature source into the in taxanes, derived from additional information in the

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TOOL FOR ADJUVANT THERAPY DECISION MAKING
literature. The details of these derivations can be found in
“Methods.” The Adjuvant! program gives the user the
efficacy of various adjuvant regimens: 1) endocrine therapy
(which refers to 5 years of adjuvant tamoxifen); 2) chemo-
therapy (polychemotherapy), either CMF-like, anthracy-
cline-based, or anthracycline- and taxane-based. These are
given by subsets defined by ER and menopausal status (the
Overview uses age ⬍ or ⱖ to 50 rather than menopausal
status). One need not accept these values but can toggle
these values or create entire sets of customized estimates of
estimates that can be saved for later use.
Resulting Graphs
The section showing the Resulting Graphs allows the
viewing of outcomes for survival in terms of OS at 10 years,
estimates of remaining life expectancy, and long-term
survival curves. It also allows outcomes to be viewed for
DFS at 10 years. The OS and DFS at 10 years are presented
as bar graphs and are the primary outputs of the program.
Projections of outcomes beyond 10 years, although inter-
esting, are speculative.
The bar graphs are used to show OS at 10 years’
follow-up. They show what percentage of patients are alive
at 10 years, what percentage die of breast cancer, what
percentage die of non– breast cancer causes of death, and an
estimate of the increased percentage of patients alive at 10
years because of specific adjuvant therapy chosen. Viewing
OS in this format allows a perspective on what role breast
cancer mortality has within the next 10 years of the patient’s
life. For older node-negative patients with small tumors, it is
often quite small in comparison with other non– breast
cancer mortality. While viewing these bar graphs, one can
toggle between different adjuvant treatment options to
examine the impact of the benefit of therapy for a variety of
therapeutic options. These graphs include text showing net
benefit to tenths of a percent. Although the projections are
not this accurate, this feature allows the physician to see
how small the outcome differences are without having
rounding errors obscure them.
The bar graphs showing DFS show what percentage of
patients are alive without breast cancer at 10 years, what
percentage are expected to relapse with breast cancer, what
percentage die of other non– breast cancer causes of death.
These estimates are shown for scenarios where adjuvant
therapy is either used or not, allowing one to view the
additional percentage of patients who remain disease-free at
10 years because of adjuvant therapy. Viewing DFS in this
format allows a perspective on the risk of relapse in the next
10 years. While viewing these bar graphs, it is possible to
toggle between different adjuvant treatment options and
examine the impact on DFS.
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987
Another format for viewing the impact of adjuvant
therapy is to view the impact on expected average remain-
ing-life expectancy. Bar graphs showing life expectancy
estimates provide the patient’s average life expectancy in
years assuming the cancer had never happened and then
allows a comparison between this figure and life expectancy
for the patient in two ways: first if she is not treated by
adjuvant therapy and then if she is treated with the selected
form of adjuvant therapy. These graphs are speculative
because they depend on unverifiable estimates of long-term
mortality rates and the assumption that there will be no
major improvements in breast cancer treatment and that the
treatment of other health problems may have major effects
on life expectancy. It seems likely that such changes will
occur incrementally. By providing the information on life
expectancy in this way, we allow the user to put into
perspective the impact of the breast cancer on the patient’s
remaining life expectancy and what the net impact of
adjuvant therapy might be. These estimates are made to
tenths of a year for the same reasons. The survival curves
show the projected survival to 30 years postdiagnosis in
scenarios in which (1) the cancer had never happened, (2)
the cancer was not treated by adjuvant therapy, and finally,
(3) the cancer was treated with the selected form of therapy.
These curves are also speculative, because of the many
uncertainties beyond 10 years’ follow-up.
Output as Hard Copy
The print option allows a combination of any of these
graphs to be printed. The bar graphs of DFS and OS are
printed in a format that has been specifically designed for
easy patient interpretation. The format and graphic presen-
tation of the printed format of Adjuvant! was evaluated
during its development. Issues of concern were (1) wording,
(2) layout, including font size and color, (3) use of bar or pie
graphs, and (4) the amount and order of information to be
presented. We first tested our Decision Guide with 24 breast
cancer patients who were returning for either adjuvant
treatment or follow-up care. They ranged in age from 47 to
74 years, were a racially diverse group, and had a wide
range of education levels. After making changes iteratively,
the format was then tested with 25 patients who were in the
process of considering their adjuvant therapy options. Ex-
amples of the type of refinements made were replacing the
term “adjuvant” therapy with “additional” therapy because
the term adjuvant was confusing to most patients. Likewise,
the term “relapse” was replaced by the phrase, “the cancer
coming back.” Originally, we labeled the graphs in terms of
percentages, however, some patients felt uncomfortable
with the term “percent.” We replaced the percentages with
a descriptive phrase: number of women out of 100. This was
988
Fig 5. Example of Adjuvant! print out. Print out also includes information
on age, tumor size, nodes involved, and ER status.
universally understood by patients. The format of the
graphics was also altered to make them easily readable. A
bar chart format was selected because patients rated this as
most easily understood (Fig 5).
Tool Bar Resources
There are a number of useful functions that can be
performed using the tool bar at the top of the main screen.
These include the ability to save individual patient analyses
in files for later reference and to control and tailor the sheets
printed out for individual patients. It is possible also to
create custom sets of efficacy estimates for specific adjuvant
therapy plans or because of disagreement with the sets
supplied by Adjuvant! (up to four such sets can be created)
and to save these sets of efficacy estimates for later use.
There are also extensive help files. The files include sections
explaining how to use the program, how it works, and how
the baseline prognostic and efficacy estimates are deter-
mined. Included in the help files is a discussion of prognos-
tic factors and how they might be used (the possibility of
using Her2, measures of proliferation, and histologic grad-
ing are discussed). There is also a section that allows direct
Internet links to treatment guidelines of the National Cancer
Institute (NCI)/Physician Data Query System and the Na-
tional Comprehensive Cancer Network, American Society
of Clinical Oncology (ASCO) prognostic factor guidelines,
Cooperative Group clinical trials, search engines for scanning
the medical literature, and sources of information for patients.
DISCUSSION
The development of the tool Adjuvant! represents an
evolutionary process.23-25 Constructing and using such a
tool requires questioning the nature of the Overview esti-
mates of the efficacy of adjuvant therapy and how to use
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RAVDIN ET AL
them, how in a practical sense prognostic information is to
be used, and ultimately, how best to present estimates of
DFS and OS to patients. Such a program has use both in a
practical and educational sense because it allows health care
professionals and their patients to understand better the
probable impact of adjuvant therapy and how this is derived
from estimates of prognosis and the efficacy of adjuvant
therapy.
The estimates of the efficacy of adjuvant therapy as
derived by Adjuvant! show that adjuvant therapy for early
breast cancer has a modest but important impact. To present
the results in quantitative terms is important because it
allows the patient to participate in the decision-making
process. The most common scenario in adjuvant therapy
decision making today is that of a patient at the age of 65
(the approximate median age of breast cancer patients) who
is ER-positive and who has a node negative, 1- to 2-cm
tumor. Adjuvant! can be used to estimate that such a patient
without therapy has approximately a 10% chance of dying
of breast cancer, a 10% chance of dying of other causes, and
an 80% chance of surviving another 10 years. Endocrine
therapy (5 years of tamoxifen) improves her chances ap-
proximately 2.4%, and combined chemoendocrine therapy
with both anthracycline-based chemotherapy regimen fol-
lowed by tamoxifen approximately 3.6%. Should such a
woman get the combined program for the 1% survival
advantage? Studies of the opinions of breast cancer patients
who have had chemotherapy suggest that many women
would select to receive chemotherapy for such a small
survival advantage, although many would not.3,26 The same
analysis done by Adjuvant! for breast cancer–free survival
at 10 years suggests a 70% breast cancer–free survival that
would be improved to 78% by tamoxifen and 10% by the
addition of chemotherapy. These general results match the
modest effects seen in clinical trials. For example, in National
Surgical Adjuvant Breast and Bowel Project trial B-16, which
compared adjuvant tamoxifen to four cycles of doxorubicin
and cyclophosphamide followed by tamoxifen in node-positive
endocrine therapy in responsive patients older than 50, modest
but significant advantages for the combined approach were
seen. The typical patient in this study was in her early 60s, had
one to three positive nodes, and a T2 primary tumor. When
these parameters are entered into Adjuvant!, the program
projects a 59% overall survival at 10 years for patients
receiving tamoxifen with an improvement of 5% for the
patients receiving the combined therapy. This is close to the
report in the trial (57% and 62% OS at 10 years for the
tamoxifen only and combined groups).
The ideal validation of results presented by Adjuvant! is
problematic because there are no population-based data-
bases that have reliable information on the crucial elements
TOOL FOR ADJUVANT THERAPY DECISION MAKING
Table 5. Benefit as Reported From Node Negative Trials With 10 Years’ Follow-up and as Indirectly Projected by Adjuvant!
Reported for the Trial Outcome (%) at 10 Years
Trial OS Benefit DFS
B14 NN 74 3 57
Obs v tamoxifen
B13 NN 74 6 57
Obs v MF
Intergroup NN 71 10 58
Obs v CMFP31
Abbreviations: NN, node negative; Obs, observed; MF, methotrexate and fluorouracil; CMFP, cyclophosphamide, methotrexate, fluorouracil, and prednisone.
needed: detailed individual staging information, breast can-
cer–specific mortality and recurrence information, and
whether and what type of systemic adjuvant therapy was
administered. The use of medical literature is also problem-
atic because series are small, and in the reports of clinical
trials, there may be biases in the type of patients entered
onto trials, particularly for patients with small, low-risk
tumors. For node-negative patients (particularly T1N0M0,
stage 1 patients), the estimates of baseline outcome and the
impact of adjuvant therapy are especially important to
validate, because for these patients the estimates are most
likely to influence their treatment decisions.
Estimates of breast cancer–specific mortality derived
from the SEER data and used by Adjuvant! reasonably fit
published estimates for small node-negative tumors. For
patients with node-negative T1a and T1b tumors, Adjuvant!
uses an estimate of 10-year breast cancer–specific mortality
of 4%. Estimates for patients receiving no systemic therapy
from a Finnish registry are 4% (n ⫽ 80) and from Memorial
Sloan-Kettering Cancer Center are 7% (n ⫽ 171). For
patients with T1c tumors, Adjuvant! uses an estimate of
10%, whereas Finnish27 and Memorial Sloan-Kettering28
estimates are 7% (n ⫽ 130) and 18% (n ⫽ 303), respec-
tively. Estimates of breast cancer–specific relapse are much
more problematic because of the widely varying definitions
of this term. In most reports, this term can be inferred from
disease-free survival estimates, but disease-free survival
estimates include events other than breast cancer recurrence,
usually counting as events deaths due to any cause and even
any second primary cancers. An estimate of 15% for stage
1 tumors from a natural history database29 of recurrence risk
at 10 years is reasonably close to that given by Adjuvant!
(18%).
Another approach to this problem is to use information
from adjuvant clinical trials that evaluated the impact of
systemic adjuvant therapy in node-negative patients. For
this approach, individual patient data were not used, but
rather published tables of characteristics of patients partic-
ipating in the trials were used to make estimates of the size
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989
Projected by Adjuvant! Outcome (%) at 10 Years
Benefit OS Benefit DFS Benefit
12 76 4 65 12
14 68 6 58 11
15 68 8 59 11
of subsets of patients on the basis of age, tumor size,
number of nodes, and ER status. The program Adjuvant!
then was used to make estimates of outcome of OS and DFS
in these subsets. A weighted average (using the size of the
subsets) was then made and could be compared with the
results of the trial.
The results of this type of analysis are shown in the Table
5. For example, in NSABP B-14, a trial examining the
effectiveness of adjuvant tamoxifen in node-negative ER-
positive patients (58% of which had stage 1 disease), the
outcomes and degree of benefit for tamoxifen as projected
by Adjuvant! corresponds within a few percent to that
observed in the trial. The fit for other recent node-negative
trials reported with 10 years’ follow-up is also reasonably
close. Although this method of validation is not ideal, it
does give some confidence that on average the projections
approximate what occurs in the clinic.
A number of simplifying approximations were made to
produce the estimates made by Adjuvant!. An ideal model
(1) would have more complex time-dependent terms for the
risk of relapse and mortality without therapy, (2) might use
terms with a difference time-dependence for patients who
received adjuvant therapy (reflecting some events being
delayed rather than prevented), and (3) might use more
complex time and tumor-dependent estimates for the effec-
tiveness of adjuvant therapy. Some of the more complex
terms (although interesting) currently are not available and
may complicate the analysis, which is already arcane but is
still understandable when given in simple terms. A criticism
of Adjuvant! is that it does not provide estimates with 95%
confidence intervals. With the large number of uncertainties
(in the data entered, in the prognostic estimates, and
estimates of efficacy), confidence intervals could not be
calculated formally. Some perception of the sensitivity of
the outcome estimates can be gained by the program
operator by entering information across the range of possi-
ble estimates.
There are several aspects of the use of the program that
can be instructive to the clinician. One of these is the PFIC.
990
The use of this tool gives insight into the dubious way
prognostic factor information is used today. The vague
terms with which prognostic factor information is typically
reported now (usually favorable or unfavorable), without
prevalence or relative risk conferred information does not
allow an intelligent use of this information. Prognostic tests
that confer modest relative risks (for example, 1.3) can
never cause more than 1.3-fold change the estimate of risk.
Even more powerful tests may have limited use. For
example, PFIC can be used to show that for the patient with
a 10% baseline risk, a test that confers a relative risk of 2.0 and
a prevalence of 50% will identify high- and low-risk subsets
with a 6.7% and 13.3% risk, only modestly different than the
baseline estimate. Indeed, the PFIC can be used to demonstrate
that for a test with a 50% positive prevalence, no matter how
great the relative risk conferred, the resulting estimate of risk of
negative outcome in the high-risk subset cannot be more that
twice the baseline risk of the group as a whole.
The inclusion of additional prognostic information may
be important, but the program does not include a specific list
of additional prognostic tests to be done (recommendations
for this can be obtained from the Web connections within
the program to the ASCO guidelines). Thus, there are often
multiple methodologies for even a single factor that is used
for refining prognostic estimates, with differing prevalence
of positive results, conferring differing relative risks, and
with differing reliabilities. Nonetheless, the inclusion of
histologic grade or some measure of proliferative rate has
wide acceptance30 and the help files provide information
about how to use this information either directly or when
using the PFIC.
There are insights into the strengths and weaknesses of
the Overviews5,6 that can be gained by working closely with
their results to construct models to project outcome. One of
these is the particular way mortality is analyzed in the
Overview. It is all-cause mortality. The analysis of PRR for
all-cause mortality is important because it shows that the
balance of effects of adjuvant therapy result in an improve-
ment in overall survival. It is not ideal because when
non– breast cancer mortality is included in the analysis, it
can confound the results (reducing the apparent breast
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RAVDIN ET AL
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