You are on page 1of 9

doi:10.1016/j.ijrobp.2005.11.

015
CLINICAL INVESTIGATION Breast
PROGNOSTIC INDEX SCORE AND CLINICAL PREDICTION MODEL OF
LOCAL REGIONAL RECURRENCE AFTER MASTECTOMY IN BREAST
CANCER PATIENTS
SKYE HONGIUN CHENG, M.D.,*
#
CHENG-FANG HORNG, M.S.,

JENNIFER L. CLARKE, PH.D.,

MEI-HUA TSOU, M.D.,

STELLA Y. TSAI, M.D.,*


#
CHII-MING CHEN, M.D.,

JAMES J. JIAN, M.D.,*


#
MEI-CHIN LIU, M.D.,

MIKE WEST, PH.D.,

ANDREW T. HUANG, M.D.,

**
AND LEONARD R. PROSNITZ, M.D.
#
Departments of *Radiation Oncology,

Research,

Pathology,

Medical Oncology, and

Surgical Oncology, Koo Foundation Sun
Yat-Sen Cancer Center, Taipei, Taiwan;

Institute of Statistics and Decision Sciences and Departments of
#
Radiation Oncology,
**Medicine, and

Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
Purpose: To develop clinical prediction models for local regional recurrence (LRR) of breast carcinoma after
mastectomy that will be superior to the conventional measures of tumor size and nodal status.
Methods and Materials: Clinical information from 1,010 invasive breast cancer patients who had primary
modied radical mastectomy formed the database of the training and testing of clinical prognostic and prediction
models of LRR. Cox proportional hazards analysis and Bayesian tree analysis were the core methodologies from
which these models were built. To generate a prognostic index model, 15 clinical variables were examined for
their impact on LRR. Patients were stratied by lymph node involvement (<4 vs. >4) and local regional status
(recurrent vs. control) and then, within strata, randomly split into training and test data sets of equal size. To
establish prediction tree models, 255 patients were selected by the criteria of having had LRR (53 patients) or no
evidence of LRR without postmastectomy radiotherapy (PMRT) (202 patients).
Results: With these models, patients can be divided into low-, intermediate-, and high-risk groups on the basis
of axillary nodal status, estrogen receptor status, lymphovascular invasion, and age at diagnosis. In the low-risk
group, there is no inuence of PMRT on either LRR or survival. For intermediate-risk patients, PMRT improves
LR control but not metastases-free or overall survival. For the high-risk patients, however, PMRT improves both
LR control and metastasis-free and overall survival.
Conclusion: The prognostic score and predictive index are useful methods to estimate the risk of LRR in breast
cancer patients after mastectomy and for estimating the potential benets of PMRT. These models provide
additional information criteria for selection of patients for PMRT, compared with the traditional selection
criteria of nodal status and tumor size. 2006 Elsevier Inc.
Breast cancer, Mastectomy, Radiotherapy, Prediction model, Prognostic score.
INTRODUCTION
Postmastectomy radiotherapy (PMRT) clearly reduces the
frequency of local regional recurrence (LRR) in high-risk
breast cancer patients (1). It also seems to impact favorably
on survival (2). The delineation of patients at high risk for
LRR is controversial, however. Conventionally, the number
of involved axillary lymph nodes and the size of the primary
tumor are considered, and PMRT is generally recommended
for those with 4 or more involved axillary lymph nodes
and/or those with large primary tumors (T3 or greater)
(35). However, three randomized trials in which a survival
benet for PMRT was demonstrated included primarily
NoteAn online CME test for this article can be taken at
www.astro.org under Education and Meetings.
Reprint requests to: Skye H. Cheng, M.D., Koo Foundation Sun
Yat-Sen Cancer Center, Department of Radiation Oncology, No.
125, Lih-Der Road, Pei-Tou District, Taipei, Taiwan. Tel: (886)
2-28970011, ext. 310; Fax: (886) 2-28972233; E-mail: skye@
mail.kfcc.org.tw
Supported in part by research funds from Koo Foundation Sun
Yat-Sen Cancer Center and in part by a grant from the National
Health Research Institutes of Taiwan (Contract Project 1997, No.
DD01-86IX-CR601S).
AcknowledgmentsThe authors thank the members of the Breast
Cancer Team at Koo Foundation Sun Yat-Sen Cancer Center: Drs.
Po-Sheng Yang and Ben-Long Yu (Department of Surgery), Drs.
H.H. Lin and M.Y. Lee (Department of Pathology), Drs. Kwan-
Yee Chan and Christopher K.J. Lin (Department of Radiology),
Drs. Tran-Der Tan, Cheng-I Hsieh, and Nei-Min Chu (Department
of Medical Oncology), and Dr. Yu-Ling Chung (Department of
Radiation Oncology) for patient care; and Yen-Chun Lin, Yueh-
Yun Yu, Yi-Wen Chang, and An-Chen Feng in the Clinical Pro-
tocol Ofce for data collection, data entry, data quality control, and
outcome analysis.
Received April 2, 2005, and in revised form Nov 15, 2005.
Accepted for publication Nov 15, 2005.
Int. J. Radiation Oncology Biol. Phys., Vol. 64, No. 5, pp. 14011409, 2006
Copyright 2006 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/06/$see front matter
1401
patients with 13 positive lymph nodes (68). Thus, a
better denition of what constitutes a patient at high risk for
LRR and who would be expected to benet from PMRT
would be valuable.
Several other prognostic factors, such as estrogen recep-
tor (ER) status, age, lymphovascular invasion (LVI), and
extracapsular extension of tumor in axillary lymph nodes
have previously been identied as predictive for LRR after
mastectomy (911). The interaction between these factors,
however, is largely unknown.
The aim of this study was to develop more sophisticated
prediction models for LRR after mastectomy, by using
readily available clinical data in a fashion analogous to the
development of the International Prognostic Index for pa-
tients with non-Hodgkins lymphomas (12). To accomplish
this, both traditional Cox proportional hazards models and
Bayesian classication trees were used to estimate the prob-
ability of LRR after mastectomy for individual breast cancer
patients (1315).
METHODS AND MATERIALS
Treatment policies
Between April 1999 and December 2001, 1,143 patients under-
went modied radical mastectomy as initial treatment for newly
diagnosed invasive breast cancer at the Koo Foundation, Sun
Yat-Sen Cancer Center in Taipei, Taiwan. Adjuvant treatment
policies were as follows.
Postmastectomy radiotherapy. Before 1997, patients received
PMRT if they had involvement of 4 or more axillary lymph nodes
or a primary tumor 5 cm in size or a resection margin positive or
close. After 1997, patients with 13 axillary lymph nodes involved
were also candidates for PMRT if combined with another risk
factor, specically a primary tumor 3 cm, ER-negative status,
age 40 years, or the presence of LVI.
The technique for PMRT included radiation elds specically
directed to the ipsilateral chest wall and internal mammary chain
and supraclavicular lymph nodes with CT-based treatment plan-
ning. The heart was largely excluded from the radiation elds. The
central lung distance of the tangents elds was limited to a max-
imum of 3 cm. Internal mammary chain nodes were either included
in wide tangent elds if the included lung was acceptable or treated
with a separate photon/electron eld. The full axilla was excluded
from the radiation elds. The dose of radiation was 4550 Gy in 25
fractions (16).
Adjuvant systemic therapy. Before 2000, node-positive patients
were treated with one of four chemotherapy regimensAC (doxoru-
Table 1. Clinical characteristics of patients in the training and
test data sets
Characteristic
Training Test
P value* (n 506) (n 504)
Age (y)
35 44 44 0.88
3640 72 74
4150 194 181
50 196 205
Menstruation status
Premenopausal 312 299 0.45
Postmenopausal 194 205
Family history
No 451 453 0.87
1st or 2nd degree 52 49
Others 3 2
Histology
Favorable

26 24 0.36
Inltrating ductal 430 416
Other invasive 50 64
Pathological tumor size
(cm)
2.0 230 227 0.89
2.0 276 277
No. of axillary nodes
dissected
10 24 15 0.32
1019 226 211
2029 192 209
30 64 69
No. of axillary nodes
positive
0 248 250 0.76
13 144 142
49 70 61
9 44 51
Extracapsular extension
Negative 378 366 0.58
Positive 121 133
Unknown 7 5
Estrogen receptor status
Negative 137 154 0.29
102 111
137 110
130 129
Lymphovascular invasion
Absent 266 268 0.35
Focal 85 100
Prominent 155 139
Nuclear grade
1 93 77 0.37
2 158 168
3 249 259
Surgical margins
Negative 493 483 0.43
Close (2 mm) 7 14
Positive 1 2
Unknown 5 5
Adjuvant radiotherapy
Yes 137 123 0.33
No 369 381
Adjuvant hormonal therapy
Yes 363 362 0.98
No 143 142
(Continued)
Table 1. Clinical characteristics of patients in the training and
test data sets (Continued)
Characteristic
Training Test
P value* (n 506) (n 504)
Adjuvant chemotherapy
Yes 369 362 0.70
No 137 142
* Chi-square test.

Favorable histology: medullary, tubular, or mucinous carcinoma.


1402 I. J. Radiation Oncology Biology Physics Volume 64, Number 5, 2006
bicin, cyclophosphamide), CMF (cyclophosphamide, methotrexate,
5-uorouracil), CAF (cyclophosphamide, doxorubicin, 5-uoroura-
cil), or CEF (cyclophosphamide, epirubicin, 5-uorouracil)as were
selected node-negative patients (those who were ER/progesterone
receptornegative or premenopausal patients with a 2-cm primary
lesion). Patients with 4 or more positive lymph nodes during this
period received A followed by CMF (17). After 2000, node-
positive patients with ER negative were treated with AC fol-
lowed by paclitaxel; node-positive patients with ER positive
were treated with A followed by CMF. Patients with 10 or more
positive nodes received dose-dense ACT.
Prognostic factors
Fifteen tumor-, patient-, and treatment-related factors were ex-
amined for their impact on LRR (Table 1). We included all
characteristics that have been previously reported in the literature
to inuence LRR, regardless of the strength of the evidence. These
factors might be characterized as patient related (e.g., age), tumor
related (e.g., ER status), or treatment related (e.g., adjuvant che-
motherapy). Of the 1,143 patients who underwent modied radical
mastectomy during the study, 1,010 patients who have data on all
six clinical risk factors (age at diagnosis, primary tumor size,
axillary lymph node status, nuclear grade, LVI, hormonal receptor
status) constitute the study group.
Statistical analysis
Two statistical approaches were used in this study; these ap-
proaches complement each other by using different types of math-
ematical models (linear and nonlinear) to characterize the relation-
ship between LR control and the prognostic factors under study. In
the rst approach, Cox proportional hazards regression models
were used to assess the prognostic signicance of risk factors (14).
All patients were stratied by lymph node involvement (4 vs.
4) and LR status (recurrence vs. control), and then, within strata,
patients were randomly assigned to one of two subsets of equal
size for model training and validation. Patient characteristics in the
training and test data sets were well balanced (Table 1). The
step-down regression analysis of LR control in the training sam-
ples evaluated all 15 prognostic variables mentioned above. Du-
ration of LR control was calculated from the rst day of treatment
until the day when chest wall or regional lymph node recurrence
was observed. Local regional control estimates were calculated
according to the methods of Kaplan and Meier (18). Logrank tests
were used to assess the statistical signicance of the difference in
the probabilities of LR control between specic patient subsets
(19). The model results were used to dene levels of risk of LR
recurrence (see below); the predictive ability of these levels was
assessed by application to the validation set.
The Kaplan-Meier estimates of LR control in specic patient
subsets were compared with results from the second statistical
approach, based on prediction tree models. These tree models
classify patients into subgroups with higher or lower probability of
LR control, according to selected risk factors (e.g., lymph node
positive 3 vs. 3, age 40 vs. 40 years). Estimates of LR
control were calculated for each subgroup.
The details of tree generation and Bayesian analysis have been
published previously (13, 20, 21). In brief, Bayesian methods of
analysis are used to t candidate tree models to the training data;
each model uses different risk factors to assign patients to sub-
groups, which vary in their probability of LR control. The best-
tting trees are selected, and from each of these trees an estimate
of LR control for each patient is calculated. This provides several
estimates of LR control for each patient; the nal estimate of LR
control for a patient is a weighted average of these estimates,
whereby the estimates from better-tting trees are given larger
weights. The risk factors used to subgroup patients in the best-
tting models provide insights into which clinical predictor vari-
ables and interactions of clinical predictor variables impact the
probability of LR control.
We selected 255 of the 1,010 patients for training and construction
of the prediction tree models. The selection criteria were patients who
had any evidence of LR recurrence within 5 years (n 53) and no
evidence of LR recurrence without PMRT for a minimum fol-
low-up of 5 years (n 202). The predictive ability of the model
to assess probability of LR control is assessed by cross-validation
on the training set.
RESULTS
Table 1 shows the clinical characteristics and treatment
parameters for the 1,010 patients in the study group, divided
equally into training and test subsets. These subsets were
well balanced with regard to these risk factors. In general,
the patients were young, with 23% aged 40 years at the
time of diagnosis. Despite this, 71% were ER positive.
Forty-nine percent were node negative, and 45% had pri-
mary tumors 2 cm in size or less.
Regarding treatment characteristics, 72% of patients re-
ceived adjuvant chemotherapy, 72% adjuvant hormonal ther-
apy, and 26% adjuvant radiotherapy. Chemotherapy regimens
consisted of CMF in 19.7%, CAF in 38.3%, CEF in 1.6%,
AC in 12%, A-CMF in 14.5%, ACT in 2.6%, dose-dense
ACT in 4.7%, and miscellaneous in 6.6%. The radiation
dose ranged from 45 to 66 Gy (median, 50 Gy).
With a median follow-up of 48 months, 869 patients (86%)
were without evidence of disease, whereas 141 (14%) had
relapsed. The initial sites of relapse were local regional in
1.6% of patients, distant in 8%, and both combined in 4%.
The 5-year probability of any LRR, either isolated or in
combination with distant metastases, was 7.2%.
Multivariate analysis of both the training data set and the
test set revealed four clinical characteristics signicantly
Table 2. Cox proportional hazards analysis of risk of 5-year
local regional recurrence in the training data set
Risk factor Hazard ratio 95% CI
Age (y)
40 vs. 40 2.5 1.15.6
Estrogen receptor status
Negative vs. positive 2.6 1.15.7
Lymph node positive
13/49/9 vs. 0 3.1/16.1/45.8 1.18.7/3.476/
11190
Lymphovascular invasion
Prominent vs. absent/focal 3.3 1.47.7
Adjuvant radiotherapy
Yes vs. no 0.05 0.010.15
Abbreviation: CI condence interval.
n 506.
1403 Prediction of LRR after mastectomy S. H. CHENG et al.
associated with LRR. These were axillary nodal status, ER
status, LVI, and age at diagnosis. In addition, the use of
adjuvant radiotherapy was signicantly associated with LR
control. The best grouping of these clinical risk factors was
age (40 vs. 40 years), ER (negative or positive), axillary
nodal involvement (0 vs. 13 vs. 49 vs. 9), and LVI
(absent/focal vs. prominent).
Hazard ratios for these risk factors are shown in Table 2.
The four pretreatment characteristics were used to design a
model to predict an individual patients risk of LRR. The
relative risks associated with each of the risk factors were
comparable (hazard ratios of 2.53.3) with the exception of
patients with 49 positive nodes or 9 positive nodes, with
hazard ratios of 16.1 and 45.8, respectively.
A prognostic index score was then developed for the risk
of LRR. The index score was dened as the sum of the
number of risk factors present with each risk factor receiv-
ing a value of 1, except for lymph node status, which was
scored as 1 for 13 nodes positive, 2 for 49 nodes positive,
and 3 for 9 nodes positive. Thus, patients could receive a
score from 0 to 6.
Risk groups were dened by comparing the relative risk
of LRR in patients with different index scores and combin-
ing categories with similar relative risks. Thus, patients
could be grouped as low risk (score 0 or 1), intermediate
risk (score 2 or 3), or high risk (score 46). These three
groups showed distinctive differences, not only in the risk of
LRR but also in terms of metastasis-free survival and over-
all survival (Figs. 1ac, Table 3).
The low-risk group (score 0 or 1) comprised 547
patients, 522 of whom did not receive PMRT and 25 of
whom did. There were no signicant differences in out-
come whether PMRT was given or not. In the interme-
diate-risk group (score 2 or 3) there were 328 patients,
126 of whom received PMRT, 202 of whom did not.
Although LRR was signicantly reduced in patients re-
ceiving PMRT (p 0.0003), there were no signicant
differences in metastasis-free survival or overall survival.
In the high-risk group (score 46) there were 135 pa-
tients, 109 of whom received PMRT, 26 of whom did
not. Postmastectomy radiotherapy signicantly improved
Fig. 1. Probability curves for (a) local regional (LR) control, (b) metastasis-free survival, and (c) overall survival, based
on the prognostic index score, which divided patients into low-, intermediate-, and high-risk groups. CI condence
interval.
1404 I. J. Radiation Oncology Biology Physics Volume 64, Number 5, 2006
LR control, metastasis-free survival, and overall survival
(p 0.0001, 0.001, and 0.0002, respectively.)
Bayesian tree analysis
To provide an initial indication of robustness and accu-
racy, we evaluated the predictive probability of LR control
for individual patients of the 255-patient training data set,
using leave-one-out cross-validation; the tree model process
was recomputed repeatedly, each time leaving out one sam-
ple and then predicting it on the basis of the rest. The
prediction tree methodology generated six best-tting tree
models (Fig. 2). These models identied 5 of the 15 candi-
date risk factors as important (lymph node status, age at
diagnosis, ER status, LVI, and primary tumor size). Three
major tree models (Trees 2, 43, and 13, weighting 42%,
33%, and 16%, respectively) are presented in Figs. 3AC.
The estimates of 5-year LR control from these trees were
averaged to produce overall estimates of 5-year LR control
for each patient (the tree numbers are automatically gener-
ated by MATLAB software; MathWorks, Natick, MA).
As shown in Fig. 3, axillary lymph node involvement is
the rst risk factor selected to split patients into high- and
low-risk subgroups, followed by age at diagnosis and ER
status. Patients with a prior condition of lymph node nega-
tive and age 35 years in Tree 13 are estimated to have a
5-year LR control probability of 79%. In contrast, patients
with 13 positive lymph nodes, age 38 years, and ER
Fig. 2. Summaries of predictor variables and the clinical tree model:
ve clinical variables (age at diagnosis, primary tumor size, lymph
node status [lnpos], estrogen status [erlevel], and lymphovascular
invasion [lvi]) (columns) that appear in the selected top trees (rows),
and the levels (boxed numbers) of the trees in which they dene node
splits. The probability of each tree and the overall probability of
occurrence of each of the clinical factors across the set of trees are also
given. Weighted average of estimates from individual trees are shown
in parentheses in the column headings; utility estimates of clinical risk
factors in tree models are shown in parentheses in the row headings.
Table 3. Five-year local regional control and survival
Group
No. of
patients
5-y LR control
probability (%)
5-y metastasis-free
probability (%)
5-y overall
survival (%)
Cox model
Low-risk patients (score 01)
No PMRT 522 98 92 95
PMRT 25 100 84 84
Total 547 98 92 95
Intermediate-risk patients (score 23)
No PMRT 202 85 81 82
PMRT 126 99 86 87
Total 328 90 83 84
High-risk patients (score 46)
No PMRT 26 36 33 21
PMRT 109 85 56 60
Total 135 77 53 54
Tree model
Low-risk patients (predictive index 0.94)
No PMRT 518 98 92 94
PMRT 33 100 82 89
Total 551 98 91 94
Intermediate-risk patients (predictive index 0.710.94)
No PMRT 173 89 83 87
PMRT 80 100 86 90
Total 253 93 86 88
High-risk patients (predictive index 0.71)
No PMRT 59 32 41 40
PMRT 147 88 65 65
Total 206 77 60 59
Abbreviations: LR local regional; PMRT postmastectomy radiotherapy.
1405 Prediction of LRR after mastectomy S. H. CHENG et al.
Fig. 3. Three most common trees: the boxes at nodes of a tree indicate the number of patients, whereas the number next to
the box represents the model-based estimate of 5-year LR control survival probability. (a) Tree 2 is the most important tree
of our tree models, weighted 42% (see Fig. 2); the rst node is number of positive axillary lymph nodes, with a cutoff value
of 3; the second nodes are age 38 years and estrogen receptor moderately positive; the third level of split is axillary lymph
node positive, followed by estrogen receptor moderately positive, and so on. (b) Tree 43 is the second most important tree,
weighted 33%; similar to Tree 2, patients initially are split by number of positive axillary lymph nodes positive, with a cutoff
value of 3; age 38 years and estrogen receptor strongly positive are the second nodes; lymph node negative and estrogen
receptor moderately positive are the third nodes, and so on. (c) Tree 13 is the third most important decision tree, consisting
of 16% of our prediction tree models, which means of lower weight in the prediction of recurrence. Patients with a prior
condition of lymph node negative and age 35 years would have a 5-year probability of LR control of 79%. Abbreviations:
ER status: negative (); node weakly positive (); node densely positive (); node strongly positive ().
1406 I. J. Radiation Oncology Biology Physics Volume 64, Number 5, 2006
moderately positive in Tree 43 have excellent 5-year esti-
mates of LR control, at 95%.
Patients with good LR control generally had a high pre-
dictive index, and patients with LR recurrence had a low
predictive index. Both prediction patterns had small prediction
uncertainty. As compared with Cox proportional hazards
models, the tree models focuses on predicting individual
risk of LR recurrence. The computer program to estimate
individual risk is available at http://www.kfsyscc.org/unit/
cpo/cpo.php. We applied the prediction tree models to all
1,010 patients to obtain a predictive index for each individ-
ual patient.
Comparing Bayesian classication tree models with Cox
proportional hazards model
A grouping of the 1,010 patients based on their individual
predictive index is shown in Table 3. A predictive index of
0.71 (high-risk group) is probably the best cutoff value for
patients to undergo PMRT; PMRT in this group improved
not only LR control but also metastasis-free and overall
survival. In contrast, patients did not obtain benet from
PMRT if their predictive indices were 0.94. For patients
with predictive indices between 0.71 and 0.94, PMRT im-
proved LR control (from 89.4% to 100%, p 0.005) but
made no difference in metastasis-free or overall survival.
Multivariate analysis of treatment effects in the high-risk
groups dened by either prognostic index score or predic-
tion tree models revealed that PMRT, adjuvant chemother-
apy, and hormonal therapy each signicantly improved LR
control. Postmastectomy radiotherapy also signicantly im-
proved metastasis-free survival and overall survival, whereas
the improvement in metastasis-free survival and overall
survival due to either adjuvant chemotherapy or hormonal
therapy is evident but not consistently signicant (Table 4).
DISCUSSION
The role of PMRT in the management of breast carci-
noma has been and is controversial since its introduction
more than 5 decades ago. It was soon established that
PMRT signicantly decreased LRR after surgery. Innumer-
able phase II studies and more than 30 randomized trials
have shown a consistent relative risk reduction in LRR (of
two thirds to three quarters), as summarized in three recent
meta-analyses (2224). The absolute benet depends, of
course, on the relative risk of an LRR, being greatest in
those patients at highest risk for LRR.
Survival benets obtained from PMRT are the center of
the controversy. Many early trials failed to show a survival
benet. The complexities of these trials and the pitfalls therein
have been extensively reviewed by Recht and Edge (25).
Three major recent trials, however, have convincingly shown
survival benets, as has a recent meta-analysis (68, 22).
Patients have generally been selected for PMRT (and
inclusion in these trials) on the basis of nodal involve-
ment, traditionally grouped as 13 nodes involved or 4
nodes positive. Increasing number of involved lymph
nodes generally correlates with both the risk of systemic
Fig. 3. (Continued)
1407 Prediction of LRR after mastectomy S. H. CHENG et al.
spread as well as that of LRR. The three trials mentioned
above, though comprising mostly patients with 13 pos-
itive nodes, either showed a greater benet for the 4
node-positive group or were insufciently powered for
subset analysis (26). An expert American Society of
Clinical Oncology (ASCO) panel developing guidelines
for PMRT concluded that although there was strong
evidence for increased local control in both nodal group-
ings, the evidence for improvement in disease-free sur-
vival and overall survival was more consistent for those
with 4 nodes involved, compared with the 13 node-
positive group. The panel concluded, the evidence was
insufcient to make recommendations for the routine use
of PMRT in patients with 13 positive nodes (5).
The panel also addressed the inuence of other tumor-
related characteristics (e.g., grade, ER status, LVI, pri-
mary size) as well as patient-related factors (e.g., age,
menopausal status) and concluded that evidence was
insufcient to know how these variables should factor
into the decision of whether to use PMRT. Further in-
vestigations in these areas were strongly recommended.
Unfortunately, evidence from phase III trials on some
of these points will not be soon forthcoming. A North
American Breast Intergroup study looking specically at
patients with 13 positive lymph nodes and randomizing
them to PMRT or not has closed owing to poor accrual.
A European study is planned but is years from comple-
tion (2).
Given this background, we set out to develop a prog-
nostic index to guide decisions regarding the use of
PMRT that might be more informative than a simple
division into 13 or 4 lymph nodes involved. Using
Cox proportional hazards analysis, we identied patient
age, ER status, and LVI, in addition to nodal status, as
important prognostic variables and were able to group
patients into three distinct groups with low, intermediate,
and high risks of LRR. Although PMRT increased local
regional control in all groups, statistically signicant
survival benets were only seen in the high-risk group
(Table 4). The great majority of patients with 4 nodes
involved fall into this high-risk group, but so do signif-
icant numbers of patients with 13 positive nodes (e.g., a
young woman with ER-negative disease with LVI and
13 nodes involved would fall into the high-risk group).
The model does suggest that PMRT is not necessary for
patients with 13 lymph nodes involved in the absence of
other risk factors.
The predictive tree model gave similar results. Only the
highest-risk group, with a predictive index of 0.71, would
experience survival benets from PMRT, although all groups
would have decreased LRR.
These results are consistent with recent calculations per-
formed by Olivotto et al. (27), suggesting a ratio between
the number of LRRs prevented and survival of approxi-
mately 4 to 5 to 1. Thus, an absolute reduction in LRR from
15%, for example, to 3% would be expected to lead to an
absolute survival benet of 2% to 3%. A demonstration of
statistically signicant survival improvement would require
thousands of patients in trials, similar to what has been
entered in trials of adjuvant systemic therapy. In patients
with a much higher risk for LRR, the absolute benet is
correspondingly greater, and larger absolute survival bene-
ts are expected as well. The ASCO expert panel concluded
that, similar to systemic therapy, it was highly likely that
PMRT achieved proportional reductions in the risk of LRR
that were the same for all treated groups, the absolute
benet depending on the relative risk of the event, as
previously stated.
In summary, we have developed a prognostic score and
predictive index for LRR based on easily obtainable clinical
information that seems to provide more information regard-
ing the risk of LRR than a simple division of patients by
primary size and the number of lymph nodes involved. This
prognostic score and predictive index might lead to im-
proved guidelines for selection of patients for PMRT (Table
5). Conrmation of these results by other groups is highly
desirable. As with adjuvant systemic therapy, the ultimate
decision as to whether to undergo PMRT rests with the
patient and relates to what level of risk she nds acceptable
and how much treatment she is willing to undertake for a
small survival benet.
Table 4. Multivariate analysis for treatment effects on local regional recurrence/metastasis-free/
overall survival in high-risk patients
Treatment factors
Hazard ratio (95% CI)
LR recurrence
Metastasis-free
survival Overall survival
By prognostic index model (n 135)
Adjuvant radiotherapy 0.16 (0.060.4) 0.4 (0.20.9) 0.36 (0.20.8)
Adjuvant chemotherapy 0.11 (0.040.3) 0.43 (0.21.1) 0.57 (0.21.3)
Adjuvant hormonal therapy 0.34 (0.140.9) 0.85 (0.51.6) 0.59 (0.31.1)
By prediction tree models (n 206)
Adjuvant radiotherapy 0.10 (0.050.2) 0.47 (0.30.8) 0.58 (0.31.0)
Adjuvant chemotherapy 0.07 (0.030.2) 0.25 (0.10.5) 0.37 (0.20.7)
Adjuvant hormonal therapy 0.24 (0.10.5) 0.68 (0.41.2) 0.49 (0.30.8)
Abbreviation as in Table 2.
1408 I. J. Radiation Oncology Biology Physics Volume 64, Number 5, 2006
REFERENCES
1. Griem KL, Henderson IC, Gelman R, et al. The 5-year results
of a randomized trial of adjuvant radiation therapy after che-
motherapy in breast cancer patients treated with mastectomy.
J Clin Oncol 1987;5:15461555.
2. Whelan T, Levine M. More evidence that locoregional radia-
tion therapy improves survival: What should we do? J Natl
Cancer Inst 2005;97:8284.
3. Overgaard M, Christensen JJ, Johansen H, et al. Evaluation of
radiotherapy in high-risk breast cancer patients: Report from
the Danish Breast Cancer Cooperative Group (DBCG 82)
Trial. Int J Radiat Oncol Biol Phys 1990;19:11211124.
4. Fowble B, Gray R, Gilchrist K, et al. Identication of a
subgroup of patients with breast cancer and histologically
positive axillary nodes receiving adjuvant chemotherapy who
may benet from postoperative radiotherapy. J Clin Oncol
1988;6:11071117.
5. Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiother-
apy: Clinical practice guidelines of the American Society of
Clinical Oncology. J Clin Oncol 2001;19:15391569.
6. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative
radiotherapy in high-risk premenopausal women with breast
cancer who receive adjuvant chemotherapy. Danish Breast
Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337:
949955.
7. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative
radiotherapy in high-risk postmenopausal breast-cancer pa-
tients given adjuvant tamoxifen: Danish Breast Cancer Coop-
erative Group DBCG 82c randomised trial. Lancet 1999;353:
16411648.
8. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and
chemotherapy in node-positive premenopausal women with
breast cancer. N Engl J Med 1997;337:956962.
9. Dunst J, Steil B, Furch S, et al. Prognostic signicance of local
recurrence in breast cancer after postmastectomy radiother-
apy. Strahlenther Onkol 2001;177:504510.
10. Katz A, Buchholz TA, Thames H, et al. Recursive partitioning
analysis of locoregional recurrence patterns following mastec-
tomy: Implications for adjuvant irradiation. Int J Radiat Oncol
Biol Phys 2001;50:397403.
11. Sundquist M, Thorstenson S, Klintenberg C, et al. Indicators
of loco-regional recurrence in breast cancer. The South East
Swedish Breast Cancer Group. Eur J Surg Oncol 2000;26:
357362.
12. A predictive model for aggressive non-Hodgkins lymphoma.
The International Non-Hodgkins Lymphoma Prognostic Fac-
tors Project. N Engl J Med 1993;329:987994.
13. Pittman J, Huang E, Nevins J, et al. Bayesian analysis of
binary prediction tree models for retrospectively sampled out-
comes. Biostatistics 2004;5:587601.
14. Cox D. Regression models and life-tables. J R Stat Soc 1972;
34:187220.
15. Huang E, Cheng SH, Dressman H, et al. Gene expression
predictors of breast cancer outcomes. Lancet 2003;361:1590
1596.
16. Cheng SH, Jian JJ, Chan KY, et al. The benet and risk of
postmastectomy radiation therapy in patients with high-risk
breast cancer. Am J Clin Oncol 1998;21:1217.
17. Cheng SH, Tsou MH, Liu MC, et al. Unique features of breast
cancer in Taiwan. Breast Cancer Res Treat 2000;63:213223.
18. Kaplan EL, Meier P. Nonparametric estimation from incom-
plete observation. J Am Stat Assoc 1958;53:457481.
19. Mantel N, Haenszel W. Chi-square test with one degree of
freedom: Extensions of the Mantel-Haenszel procedure. J Am
Stat Soc 1963;58:690700.
20. Pittman J, Huang E, Dressman H, et al. Integrated modeling of
clinical and gene expression information for personalized pre-
diction of disease outcomes. Proc Natl Acad Sci U S A 2004;
101:84318436.
21. Kass R, Raftery A. Bayes factors. J Am Stat Assoc 1995;90:
773795.
22. Whelan TJ, Julian J, Wright J, et al. Does locoregional radi-
ation therapy improve survival in breast cancer? A meta-
analysis. J Clin Oncol 2000;18:12201229.
23. Favourable and unfavourable effects on long-term survival of
radiotherapy for early breast cancer: An overview of the
randomised trials. Early Breast Cancer Trialists Collaborative
Group. Lancet 2000;355:17571770.
24. Cuzick J, Stewart H, Rutqvist L, et al. Cause-specic mortal-
ity in long-term survivors of breast cancer who participated in
trials of radiotherapy. J Clin Oncol 1994;12:447453.
25. Recht A, Edge SB. Evidence-based indications for postmas-
tectomy irradiation. Surg Clin North Am 2003;83:9951013.
26. Ragaz J, Olivotto IA, Spinelli JJ, et al. Locoregional radiation
therapy in patients with high-risk breast cancer receiving
adjuvant chemotherapy: 20-year results of the British Colum-
bia randomized trial. J Natl Cancer Inst 2005;97:116126.
27. Olivotto IA, Truong PT, Chua B. Postmastectomy radiation
therapy: Who needs it? J Clin Oncol 2004;22:42374239.
Table 5. Impact of postmastectomy radiotherapy on patient outcomes, according to prognostic score and predictive index
Prognostic score
or predictive
index
Improvement
of LR
control
Improvement
of
metastasis-free
survival
Improvement
of overall
survival
2/0.94 No No No
23/0.710.94 Yes No No
3/0.71 Yes Yes Yes
Abbreviation as in Table 3.
1409 Prediction of LRR after mastectomy S. H. CHENG et al.