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95
Outcome of Patients with Metastatic Breast
Carcinoma Treated at a Private Medical
Oncology Clinic
William F. Anderson, M.D., M.P.H.1
James E. Reeves, M.D.2
Abdalla Elias, M.D.3
Hans (J) Berkel, M.D., Ph.D.4
1
National Cancer Institute/Division of Cancer Prevention, Preventive Oncology Branch, Bethesda,
Maryland.
2
Cancer Care Associates, Oklahoma City, Oklahoma.
3
Pathology Department, Glenwood Regional Medical Center, West Monroe, Louisiana.
4
Section of Cancer Control and Prevention, FeistWeiller Cancer Center, Louisiana State University
Medical Center-Shreveport, Shreveport, Louisiana.
BACKGROUND. Metastatic breast carcinoma usually is fatal. The median survival
after recurrence is 2 years. Five-year survival after recurrence is approximately
10 –20%. Although encouraging data have been reported from clinical trials, two
issues confound the translation of clinical research to the general medical community: patient selection bias and the absence of untreated controls. Therefore,
the authors examined their community-based metastatic breast carcinoma patients, comparing their results with reports from clinical trials and with untreated
historic controls.
METHODS. This was a nonconcurrent cohort study of 407 community-based metastatic breast carcinoma patients treated at the authors’ private medical oncology
clinic in northeast Louisiana. Prognostic variables were correlated with survival
time.
RESULTS. The median age of the patients at the time of diagnosis of breast
carcinoma was 61 years. The median age at the time of first recurrence was 65
years. The median overall survival and median survival after recurrence were 4.5
years and 20.1 months, respectively. The 5-year and 10-year survival rates were
17% and 2.5%, respectively.
CONCLUSIONS. Although clinical trial participants and the authors’ private practice
cohort are incommensurable, outcomes in these disparate groups were similar but,
unfortunately, not much different from those of untreated historic controls. Cancer
2000;88:95–107. © 2000 American Cancer Society.
KEYWORDS: metastatic breast carcinoma, chemotherapy, endocrine therapy, patient selection bias, generalizability.
B
For their review, comments, and suggestions, the
authors are indebted to Douglas L. Weed, M.D.,
Ph.D. (NCI/DCP/Preventive Oncology Branch, Bethesda, MD) and Kenneth C. Chu, Ph.D. (NCI/OSPR,
Bethesda, MD).
Address for reprints: William F. Anderson, M.D.,
M.P.H., NCI/DCP/Preventive Oncology Branch, Executive Plaza South, Suite T41, 6120 Executive
Boulevard, MSC 7105, Bethesda, MD 208927105.
Received February 18, 1999; revision received
May 26, 1999; accepted July 12, 1999.
© 2000 American Cancer Society
reast carcinoma is a major public health problem. Although modern methods of early detection, intervention, and postoperative
treatment have improved the prognosis for patients with primary
breast carcinoma,1,2 not all patients are cured. Some women present
de-novo with metastatic breast carcinoma (MBC), whereas others
develop recurrent MBC.
Historically, the median survival for MBC patients is a modest 2
years, with 1–3% of patients achieving a long term cure.3–7 Front-line,
conventional dose anthracycline and alkylating agent-based chemotherapy protocols produce 50 –90% overall response rates,3 but responses usually are temporary. For patients with MBC who are resistant to standard cytotoxic chemotherapy, there is a 20 –25% partial
response with salvage treatment8 and little hope of a cure.9 –13 Consequently, we are witnessing an enormous effort to increase the
treatment options for these patients with novel drug combinations
and treatment strategies.14 –20 The medical literature reports encour-
96
CANCER January 1, 2000 / Volume 88 / Number 1
aging data from both standard dose and high dose
clinical trials;5,16,21 however, clinical research may not
transfer to community-based breast carcinoma patients.22–24 Randomized trials have two serious flaws
that threaten extrapolation to the general medical
community: patient selection bias and the lack of untreated controls.
To ensure patient safety and internal validity,
clinical trial participation is dependent on rigorous
eligibility criteria. These criteria may introduce systematic patient selection favoring the young,
healthy, wealthy, and chemosensitive patient who is
willing and able to travel for treatment.5,6,25–29 Although the experimental method of the randomized
clinical trial is the preferred study design for internal validity and is the “gold standard” for evaluating
therapeutic efficacy,30,31 patient selection bias
threatens external validity and generalizability to
the global breast carcinoma population.
In addition and for many appropriate reasons,
MBC clinical trials do not include untreated reference
patients. Although the strongest possible evidence of
therapeutic effect would come from a prospective trial
that randomized a test regimen against symptomatic
care,32 such a study would be unethical. Nonetheless,
missing control data confounds extrapolation to the
public, because untreated patients provide the backdrop against which we judge the true benefits of a
therapeutic response.23,33 We are aware of the limitations of historic controls;34 however, without the notreatment control arm, we have lost a valuable means
of evaluating clinical research.35 Therefore, we compared the outcomes of patients with MBC in our community-based medical oncology clinic with the outcomes of untreated historic controls and with the
results from clinical trials.
MATERIALS AND METHODS
The Hematology/Oncology Clinic was a communitybased, private medical oncology clinic that operated
in northeast Louisiana for 14 years, from 1981 to 1995.
In 1990, we established the Hematology/Oncology Database (HODB), an observational data bank containing every breast carcinoma patient treated in the Hematology/Oncology Clinic. Data were collected
retrospectively for patients who were diagnosed prior
to 1990 and prospectively thereafter. For each patient,
demographic as well as clinicopathologic prognostic
information was obtained from multiple sources, including patient history and physical examinations, office and hospital records, roentgenographic and
pathologic reports, and data from the Northeast Louisiana Regional Tumor Registry.
For women who had not received long term fol-
low-up in the clinic, self-administered mail surveys
were obtained annually. Nonrespondents were contacted by telephone. Reported recurrences were confirmed with the patient and/or her physician. Roentgenographic and pathologic reports corroborated all
recurrences, when available. We used the 1977 International Union Against Cancer criteria to determine
responses to MBC treatment.36 A complete response
(CR) was the disappearance of all known disease with
no evidence of disease (NED). A partial response (PR)
required a decrease . 50% in measurable lesions and
no new lesions. No response showed no change or
could not be determined.
Patients
Most of the patients in the Hematology/Oncology
Clinic were assembled through physician referral: A
few were accrued through self-referral. Consistent
with a “real world” private medical oncology clinic, we
nonconcurrently managed patients with primary
breast carcinoma or MBC. We excluded no one from
private practice or from the HODB, but this report
includes only those women with MBC (n 5 407
women) at the time of last follow-up (December,
1998).
Although all MBC patients visited the clinic sometime during the period 1981–1995, the dates of initial
diagnoses and recurrence overlapped this period. The
initial dates of diagnosis of primary breast carcinoma
ranged from April 1958 to March 1995. The dates of
systemic recurrence varied from July 1974 to November 1998.
The 407 MBC patients presented to our clinic in
three different ways. One group (n 5 61 patients; 15%)
presented with de novo TNM Stage IV disease.37 A
second group (n 5 188 patents; 46%) presented to the
clinic with systemic recurrence. For this second group,
primary breast carcinoma care was given elsewhere
that, in some instances, preceded recurrence by many
years. The median disease free interval (DFI; date of
recurrence minus the date of diagnosis of primary
breast carcinoma) was 3.2 years (range, , 1 year to 27
years). Twenty-five patients experienced disease recurrence .10 years after the date of diagnosis of primary breast carcinoma. Past medical history and past
medical records documented initial pathologic diagnoses, prognostic factors, and adjuvant treatment. A
third group (n 5 158 patients; 39%) came to our clinic
without MBC but suffered a later systemic recurrence.
Many patients in this last group received adjuvant
hormonal and/or chemotherapy in our office, whereas
others were followed without postoperative treatment.
However, none of the patients in the third group had
MBC on first presentation to our clinic; that is, they all
Metastatic Breast Carcinoma/Anderson et al.
97
FIGURE 1.
Kaplan–Meier productlimit analysis of 407 patients with metastatic breast carcinoma (MBC).
experienced disease recurrence after their initial visit
to the Hematology/Oncology Clinic. In this third
group, MBC was not always treated in the Hematology/Oncology Clinic; that is, some patients received
therapy in other clinics or in referral centers.
Notwithstanding these varied presentations, the
407 MBC patients from the HODB were analyzed as a
single cohort. The date of diagnosis of primary breast
carcinoma was the starting point for this study. The
date of study closure (or the date of last follow-up) was
December 1998.
Demographic and Clinicopathologic Characteristics
Demographic and clinicopathologic data were examined as adjusted and unadjusted categoric variables.
Demographic information was patient age at the time
of initial diagnosis (# 50 years vs. . 50 years) and race
(black vs. white). Patient age . 50 years was our surrogate measure for postmenopausal status. Traditional clinicopathologic prognostic factors included
TNM tumor size (T4, T3, T2, and T1) and lymph node
status (. 3, 1–3, and 0 positive axillary lymph nodes).
Estrogen receptor status was coded as positive versus
negative. Chemotherapy and hormonal treatments
both before (adjuvant) and after disease recurrence
were coded yes versus no. Chemotherapy was classified further as cyclophosphamide, methotrexate, and
5-fluorouracil (CMF) or doxorubicin-based chemotherapy.
Outcome
For each patient, we recorded the date of birth, the
date of diagnosis of primary breast carcinoma, the
date of disease recurrence, and the date of death or of
last contact if the patient was still living. Primary outcome measures included survival times: DFI, survival
after recurrence (SAR), and overall survival (OS). DFI
was the time between the date of diagnosis of primary
breast carcinoma and the date of first systemic recurrence. Women with de novo Stage IV disease had no
DFI.36
The site of recurrence was categorized as either
visceral (pulmonary, pleura, hepatic, brain, bone marrow, and other), bone, locoregional, or other. Breast
recurrences (ipsilateral or contralateral) were not
coded as recurrences. Women with breast recurrences
were not censored from the study: They were followed
until systemic recurrence. We calculated SAR as the
interval between the date of recurrence and the date
of death or of the last contact for living patients.
OS was the interval between date of diagnosis and
the date of death from any cause or the date of last
contact. OS corrected for cause of death determined
cause specific mortality. Death without evidence of
MBC was coded death-NED.
Statistical Analysis
Data were entered into a personal computer with Microsoft Windows 98 operating system (Microsoft
Corp., Redmond, WA). The database was compiled in
Microsoft Access 97 for Windows. Recorded information was checked repeatedly for consistency and accuracy. Statistical analyses and graphs were generated
with Statistica for Windows, version 5.1 (Statsoft, Inc.,
Tulsa, OK).38
OS and SAR (Fig. 1) were estimated with the
Kaplan–Meier product-limit method.39 The stratified
log-rank test was used to compare survival distributions in two samples (Fig. 2).40 The Cox proportional
hazards model was used to generate unadjusted and
adjusted hazard ratios, which are expressed as the
relative risk.41 The risk of a given prognostic variable is
displayed relative to the reference variable, which has
98
CANCER January 1, 2000 / Volume 88 / Number 1
FIGURE 2.
Survival after recurrence
for patients who developed metastatic
breast carcinoma prior to 1985 and after
1990.
a value of 1.00 and is the last entry of each category
(Table 2).
With logistic regression, we calculated unadjusted
and adjusted correlations, which are expressed as
odds ratios.42 Contingency tables (Tables 3 and 4)
were arranged to demonstrate the odds of dependent,
dichotomized variables that had a given prognostic
factor relative to the reference variable; i.e., 1.00, the
last entry of each category. Relative risk and odds
ratios were presented with 95% confidence intervals
and P values. All P values were two-sided: P values #
0.05 were considered to be statistically significant.
RESULTS
Seven hundred ninety-seven (797) breast carcinoma
patients were treated in the Hematology/Oncology
Clinic between 1981 and 1995 and were entered into
the Hematology/Oncology data base (HODB). This
breast carcinoma cohort comprised 13% of our total
private practice patient base and 25% of all breast
carcinoma patients in Northeast Louisiana, based on
data from the Northeast Louisiana Tumor Registry.
Currently, 390 breast carcinoma patients (49.8%) remain recurrence free. Four hundred seven patients
(51.1%) have MBC and are the subject of this report.
Demographic and Clinicopathologic Characteristics
At the time of diagnosis of primary breast carcinoma,
the median age of the patients was 61 years (range,
21– 88 years). One hundred eleven patients (27%) were
age # 50 years. Almost 75% (n 5 296 patients; 73%)
were age . 50 years. Three hundred thirty-two patients (82%) were white, and 74 patients (18%) were
black (see Table 1).
The majority of the tumors (n 5 362 tumors; 89%)
were infiltrating ductal carcinoma of no special type.43
The initial median tumor greatest dimension was 3.0
cm, with a range from 0.3 cm to .10 cm. Most of the
primary tumors were T1 lesions (n 5 100 tumors; 25%)
or T2 (n 5 167 tumors; 41%). In 18 tumors, the tumor
size was unknown or was different than T1–T4. One
hundred fifty-one patients (37%) had negative axillary
lymph nodes at the time of diagnosis of primary breast
carcinoma. Two hundred forty-nine patients (61%)
were lymph node positive: 100 with 1–3 axillary lymph
nodes and 149 with . 3 axillary lymph nodes.
We were able to determine the initial TNM stage
in all but 7 patients, yielding a successful staging rate
of 98%. Early-stage tumors (Stage 0 and I) comprised a
minority of the primary breast carcinomas (n 5 45
patients; 11%). Half of the MBC cohort (n 5 202 patients; 50%) presented initially with TNM Stage II disease. Stage III disease represented a large fraction of
the cohort (n 5 92 patients; 23%). Sixty-one patients
had de novo Stage IV disease.
One hundred seventeen (29%) tumors were estrogen receptor negative, 172 (42%) were positive, and
118 (29%) were unknown. Many of the patients with
unknown hormonal receptors developed primary
breast carcinoma prior to 1980, before the routine
measurement of estrogen and progesterone receptors.
At the time of initial systemic recurrence, the median age of patients was 65 years (range, 23–90 years).
The median DFI was 25 months (range, 0 days to 27
years). The DFI was #24 months for 198 patients
(49%) and .24 months for the remaining 209 patients
(51%). There were 193 visceral recurrences (47%), 130
bone recurrences (32%), and 82 (20%) locoregional
recurrences.
Metastatic Breast Carcinoma/Anderson et al.
TABLE 1
Demographic and Clinicopathologic Characteristics for 407 Patients
with Metastatic Breast Carcinoma
Characteristic
Total
Percent
Sample size
Age at the time of diagnosis (yrs)
#50
.50
Race
Black
White
Other
Initial TNM tumor size
T4
T3
T2
T1
Other or unknown
Initial axillary lymph nodes
.3
1–3
0
Unknown
Initial TNM stage
0
I
II
III
IV
Unknown
Estrogen receptor status
Negative
Positive
Unknown
Disease free interval (months)
#24
.24
Site of systemic recurrence
Visceral
Bone
Locoregional
Other
Adjuvant radiotherapy
Yes
No
Unknown
Adjuvant systemic therapy
Yes
No
Unknown
Response to MBC treatment
Yes
No
Unknown
407
100.0
111
296
27.3
72.7
74
332
1
18.2
81.6
0.2
75
47
167
100
18
18.4
11.5
41.0
24.6
4.4
149
100
151
7
36.6
24.6
37.1
1.7
4
41
202
92
61
7
1.0
10.1
49.6
22.6
15.0
1.7
117
172
118
28.7
42.3
29.0
198
209
48.6
51.4
193
130
82
2
47.4
31.9
20.1
0.5
138
262
7
33.9
64.4
1.7
220
185
2
54.1
45.5
0.5
142
130
135
34.9
31.9
33.2
MBC: metastatic breast carcinoma.
Treatment
At the time of diagnosis of primary breast carcinoma,
adjuvant radiotherapy was given to 138 patients (34%).
More than half (n 5 220 patients; 54%) had adjuvant
systemic hormonal therapy and/or chemotherapy.
99
One hundred forty patients (34%) received postoperative hormonal treatment: 138 with tamoxifen and 2
with oophorectomy. One hundred thirty-eight patients (34%) received adjuvant systemic chemotherapy. Chemotherapy protocols included CMF for 60
patients, doxorubicin-based regimes for 61 patients,
and less common programs, containing thiotepa and
melphalan, for 17 patients.
At the time of initial systemic recurrence, treatment after recurrence in our clinic consisted of systemic hormonal therapy and/or chemotherapy with or
without symptomatic radiotherapy. Patients with nonlife-threatening postmenopausal MBC were treated
with front-line antihormonal therapy; i.e., tamoxifen
or megestrol acetate. Initial systemic chemotherapy,
including CMF and doxorubicin-based protocols, was
reserved for premenopausal patients, visceral recurrences, or antihormonal failures.
Some women received MBC treatment elsewhere
both before and after closure of the Hematology/Oncology Clinic. Outside office records have not always
permitted an accurate assessment of response to therapy. Other patients are actively receiving chemohormonal therapy, and it is too early to judge their response to treatment. Consequently, large amounts of
MBC treatment-related data were incomplete (n 5 135
patients; 33%).
As of the date of last follow-up (December 1998),
there was sufficient information on 272 patients (67%)
to judge their response to systemic treatment after
disease recurrence. One hundred forty-two patients
(35%) had either a partial or complete response, and
130 patients (32%) did not respond.
Outcome
Outcome-related follow-up was 100% complete. Calculated from the dates of diagnosis to the date of study
closure, the median follow-up for this analysis was 13
years (range, 4 – 41 years). There were 35 living MBC
patients and 372 deceased MBC patients. The median
OS estimated with Kaplan–Meier plots was 4.5 years
(Fig. 1).
The median SAR was 20.1 months (range, 0 days
to 17 years) (Fig. 1). Seventy patients (17%) achieved
long term survival after recurrence, defined as SAR $
5 years. Fifty-six long term survivors have died: 51 with
MBC and 5 with NED. Ten patients (2.5%) are living
$10 years after systemic recurrence.
Although the treatment philosophy was consistent during the period of clinic operation, 1981–1995,
we noted a temporal shift for SAR (Fig. 2). SAR worsened in later years. The SAR for women who experienced disease recurrence after 1990 and for those who
100
CANCER January 1, 2000 / Volume 88 / Number 1
experienced disease recurrence before 1985 was 15.8
months and 27.4 months, respectively (P , 0.001).
vant chemotherapy (yes vs. no) was the only statistically significant variable (P , 0.001).
Unadjusted and Adjusted Cox Proportional Hazards
Model for SAR
DISCUSSION
Table 2 displays unadjusted SAR by prognostic variables. The shortened median SAR was associated with
increased hazard ratio (increased relative risk) for
black women compared with white women, larger
tumor sizes, .3 positive axillary lymph nodes compared with negative lymph nodes, and negative estrogen receptor levels. Increased relative risk also was
observed for short DFI (#24 months vs. .24 months),
site of systemic recurrence (visceral and bone disease
vs. locoregional disease), adjuvant chemotherapy (yes
vs. no), and response to MBC treatment (yes vs. no). In
a multivariate (adjusted) model, statistical significance
was maintained for initial lymph node status, DFI, site
of systemic recurrence, and response to MBC treatment (Table 2).
Unadjusted and Adjusted Correlations for Short Term
Survivors versus Long Term Survivors after Disease
Recurrence
We investigated short term survivors (#2 years) compared with long term survivors ($5 years) (Table 3).
Univariate (unadjusted) analysis revealed that short
term survivors, compared with long term survivors,
had a greater likelihood of being black, having TNM
T4 lesions, having .3 axillary lymph nodes, and being
estrogen receptor negative. Short term survivors also
had a greater likelihood of having visceral and bone
recurrences versus locoregional recurrences, having
had adjuvant systemic chemotherapy, and having responded to MBC treatment. In the multivariate (adjusted) model (Table 3), correlation with site of systemic recurrence, adjuvant systemic therapy, and
response to MBC treatment remained statistically significant.
Unadjusted and Adjusted Correlations for Early versus
Late Systemic Recurrence
We examined later MBC diagnosis (after 1990) versus
earlier diagnosis (before 1985) with prognostic variables (Table 4). Unadjusted odds ratios demonstrated
no secular difference in patient age at the time of
diagnosis of primary breast carcinoma, TNM tumor
size, initial axillary lymph node status, or response to
MBC treatment. However, women who were diagnosed after 1990 versus women who were diagnosed
prior to 1985 were more likely to be estrogen receptor
negative, to have visceral and bone metastases versus
locoregional metastases, and to have had adjuvant
chemotherapy. In the adjusted model (Table 4), adju-
MBC is a heterogeneous disease with an acknowledged 2-year median SAR. Decades of clinical research
have focused on the translation of systemic treatment
into the general medical community with the expectation of improved outcome. However, in our community-based oncology clinic, we noted a median SAR of
,2 years and an adverse secular trend toward shorter
survival times.
SAR in the Hematology/Oncology clinic was correlated with race, TNM tumor size, axillary lymph
node status, estrogen receptor status, DFI, site of systemic recurrence, prior adjuvant systemic therapy,
and response to MBC treatment. In multivariate models, the strongest predictors of SAR were the site of
recurrence and response to MBC treatment (Table 2).
For patients with MBC after 1990, SAR was 15.8
months compared with 27.4 months for women with
MBC before 1985 (Fig. 2). History of adjuvant systemic
therapy was the only significant variable in the adjusted model (Table 4). We suspect a causal association between adjuvant chemotherapy and the negative temporal trend.
Although the MBC populations studied in earlier
reviews rarely received adjuvant therapy,44 there is
little doubt that SAR is compromised by adjuvant
treatment.4 Adjuvant treatment may induce acquired
resistance or select resistant malignant clones;45,46
however, for whatever reason, recurrence after adjuvant treatment identifies a subgroup of patients with a
lower response to further therapy and shorter survival
after first disease recurrence.47
After 1990, 74% of our MBC patients had a history
of prior adjuvant hormonal therapy or systemic chemotherapy. Prior to 1985, 67% of the women were
hormonal and/or chemotherapy naı̈ve. Similar to our
study, Debonis et al. noted a negative secular trend in
median survival after disease recurrence.35 SAR decreased from 31.97 months to 18.72 months from 1955
to 1980, but those authors did not comment on the
effect of adjuvant treatment.35 Clark et al. observed a
negative association of adjuvant treatment with SAR
but reported the disappearance of statistical significance in their multivariate model.4 They postulated
that the decision to administer adjuvant therapy was
based on colinear factors, such as lymph node status
and estrogen receptor status. However, Clark et al.’s
explanation would not explain our finding, because
tumor size and lymph node status were similar before
1985 and after 1990 (Table 4). The choice to administer adjuvant chemotherapy probably was related more
Metastatic Breast Carcinoma/Anderson et al.
101
TABLE 2
Cox Proportional Hazards Model for Survival after Recurrencea
Variable
Unadjusted relative risk
Sample size
Age at the time of diagnosis (yrs)
#50
.50
Race
Black
White
Other
Initial TNM tumor size
T4
T3
T2
T1
Other or unknown
Initial axillary lymph nodes
.3
1–3
0
Unknown
Estrogen receptor status
Negative
Positive
Unknown
Disease free interval (months)
#24
.24
Site of systemic recurrence
Visceral
Bone
Locoregional
Other
Adjuvant systemic therapy
Yes
No
Other
Response to MBC treatment
Yes
No
Unknown
Adjusted relative risk
Race (black vs. white)
Initial TNM tumor size (T4 vs. T1)
Initial TNM tumor size (T3 vs. T1)
Initial lymph node status (.3 vs. 0)
Estrogen receptor status (negative vs. positive)
Disease free interval (#24 months vs. .24 months)
Site of systemic recurrence (visceral vs. locoregional)
Site of systemic recurrence (bone vs. locoregional)
Adjuvant systemic therapy (yes vs. no)
Response to MBC treatment (yes vs. no)
Total
Median SAR
(months)
Relative risk
95% CI
P value
407
20.1
—
—
—
111
296
23.5
18.3
0.90
1.00
0.71–1.13
—
0.35
—
74
332
1
14.8
21.8
—
1.41
1.00
—
1.08–1.84
—
—
0.01
—
—
75
47
167
100
18
12.6
21.0
23.2
22.4
1.87
1.54
1.06
1.00
1.35–2.58
1.07–2.21
0.81–1.38
—
,0.001
0.02
0.68
—
149
100
151
7
16.2
24.2
23.2
1.49
0.94
1.00
1.18–1.90
0.72–1.23
—
,0.001
0.64
—
117
172
118
11.6
23.3
1.56
1.00
1.22–2.01
—
,0.001
—
198
209
16.6
24.8
1.46
1.00
1.19–1.79
—
,0.001
—
193
130
82
2
13.2
22.6
33.2
1.98
1.50
1.00
1.50–2.60
1.12–2.02
—
,0.001
,0.01
—
220
185
2
23.8
28.9
1.47
1.00
1.19–1.81
—
,0.001
—
142
130
135
38.2
10.9
—
0.24
1.00
—
0.18–0.32
—
—
,0.001
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
1.25
1.28
0.87
1.49
1.09
1.49
3.62
1.70
1.26
0.24
0.83–1.88
0.85–1.93
0.53–1.43
1.04–2.11
0.78–1.53
1.07–2.07
2.32–5.67
1.10–2.62
0.87–1.82
0.16–0.35
0.29
0.24
0.57
0.03
0.61
0.02
,0.001
0.02
0.23
,0.001
SAR: survival after recurrence; CI: confidence interval; MBC: metastatic breast carcinoma.
a
Hazard ratios are expressed as relative risk.
102
CANCER January 1, 2000 / Volume 88 / Number 1
TABLE 3
Demographic and Clinicopathologic Characteristics for Survival after Recurrence (<2 years vs. >5 years)a
Survival after relapse
Variable
Unadjusted odds ratio
Sample size
Actuarial median SAR (months)
Age at the time of diagnosis (yrs)
#50
.50
Race
Black
White
Initial TNM tumor size
T4
T3
T2
T1
Other or unknown
Initial axillary lymph nodes
.3
1–3
0
Unknown
Estrogen receptor status
Negative
Positive
Unknown
Site of systemic recurrence
Visceral
Bone
Locoregional
Other
Adjuvant systemic therapy
Yes
No
Other
Response to MBC treatment
Yes
No
Unknown
Adjusted odds ratio
Race (black vs. white)
Initial TNM tumor size (T4 vs. T1)
Initial axillary lymph nodes (.3 vs. 0)
Estrogen receptor status (negative vs. positive)
Site of systemic recurrence (visceral vs. locoregional)
Site of systemic recurrence (bone vs. locoregional)
Adjuvant systemic therapy (yes vs. no)
Response to MBC treatment (yes vs. no)
<2 yrs
>5 yrs
Odds ratio
95% CI
P value
268
11.3
70
78.1
—
—
—
—
—
,0.001
69
199
17
53
1.08
1.00
0.58–1.99
—
0.80
—
54
214
5
65
3.28
1.00
1.25–8.57
—
0.02
—
61
34
102
60
11
3
5
37
21
4
7.12
2.38
0.96
1.00
—
2.01–25.24
0.82–6.91
0.52–1.81
—
—
,0.01
0.11
0.91
—
—
113
60
91
4
13
21
34
2
3.25
1.07
1.00
—
1.61–6.53
0.57–2.01
—
—
,0.001
0.84
—
—
97
107
64
10
31
29
2.81
1.00
—
1.30–6.06
—
—
,0.01
—
—
140
88
39
1
22
20
27
1
4.41
3.05
1.00
—
2.26–8.60
1.52–6.09
—
—
,0.001
,0.01
—
—
167
99
2
21
49
0
3.94
1.00
—
2.22–6.96
—
—
,0.001
—
—
62
113
93
46
5
19
0.06
1.00
—
0.02–0.16
—
—
,0.001
—
—
—
14.00
0.46
1.87
25.25
5.62
5.75
0.04
—
0.82–240
1.00
0.07
0.56–6.30
4.81–132.6
1.36–23.22
1.59–20.76
0.01–0.19
0.31
,0.001
0.02
,0.01
,0.001
1.64
—
—
0.44–6.07
—
—
SAR: survival after recurrence; CI: confidence interval; MBC: metastatic breast carcinoma.
a
Correlations are expressed as odds ratios.
to the date of disease recurrence. We established the
Hematology/Oncology Clinic in 1981. Many patients
who experienced recurrences prior to 1985 simply
were never offered adjuvant treatment for primary
breast carcinoma.
Our study has several weaknesses. First, the
HODB was a retrospective series of consecutive cases:
a longitudinal study with uncontrollable vagaries and
biases.48 We bring creditability to the project with
meticulous record keeping (e.g., the 100% complete
Metastatic Breast Carcinoma/Anderson et al.
103
TABLE 4
Demographic and Clinicopathologic Characteristics for Temporal Shift (>1990 vs. <1985)a
Variable
Unadjusted odds ratio
Sample size
Actuarial median SAR (months)
Age at the time of diagnosis (yrs)
#50
.50
Race
Black
White
Other
Initial TNM tumor size
T4
T3
T2
T1
Other or unknown
Initial axillary lymph nodes
.3
1–3
0
Unknown
Estrogen receptor status
Negative
Positive
Unknown
Site of systemic recurrence
Visceral
Bone
Locoregional
Other
Adjuvant systemic therapy
Yes
No
Other
Response to MBC treatment
Yes
No
Unknown
Adjusted odds ratio
Race (Black vs. White)
Estrogen receptor status (negative vs. positive)
Site of systemic recurrence (visceral vs. locoregional)
Site of systemic recurrence (bone vs. locoregional)
Adjuvant systemic therapy (yes vs. no)
>1990
<1985
Odds ratio
95% CI
P value
154
15.8
96
27.4
—
—
—
—
—
,0.001
49
105
24
72
1.40
1.00
0.79–2.49
—
0.25
—
35
118
1
8
88
0
3.26
1.00
—
1.44–7.41
—
—
,0.01
—
—
35
17
59
39
4
9
11
47
22
7
2.19
0.87
0.71
1.00
—
0.89–5.42
0.35–2.20
0.37–1.36
—
—
0.09
0.77
0.30
—
—
63
43
47
1
37
20
36
3
1.30
1.65
1.00
—
0.72–2.37
0.83–3.28
—
—
0.38
0.15
—
—
49
85
20
27
21
48
0.45
1.00
—
0.23–0.88
—
—
0.02
—
—
80
51
22
1
39
29
28
0
2.61
2.24
1.00
—
1.32–5.15
1.08–4.62
—
—
0.01
0.03
—
—
115
39
0
31
63
2
5.99
1.00
—
3.40–10.55
—
—
,0.001
—
—
49
47
58
39
32
25
0.86
1.00
—
0.46–1.59
—
—
0.62
—
—
—
—
—
—
—
—
—
—
—
—
2.46
0.54
2.66
1.85
7.78
0.88–6.89
0.25–1.18
0.98–7.20
0.64–5.37
3.59–17.04
0.08
0.12
0.053
0.26
,0.001
CI: confidence interval; SAR: survival after recurrence; MBC: metastatic breast carcinoma.
a
Correlations are expressed as odds ratios.
follow-up and 98% successful TNM staging). Nevertheless, accurate records cannot correct an obvious
systematic error: The Hematology/Oncology Clinic
was a referral-based private practice in the rural
Southeast.
Our clinic physicians did not recruit, randomize,
or select our cohort of patients in any way; nonetheless, the patients were chosen for us. Consulting physician preferences as well as the socioeconomic fac-
tors in the community defined a vague sampling
method. Although this method of patient selection is
not ideal and clearly is subject to bias, patient accrual
through physician referral is representative of a “realworld” situation and not is unique to our northeast
Louisiana referral base. Consistent with a medical oncology private practice, patients were sent to us for the
administration of endocrine therapy and/or cytotoxic
chemotherapy.
104
CANCER January 1, 2000 / Volume 88 / Number 1
TABLE 5
Comparison of Survival for Metastatic Breast Carcinoma Patients Treated with Hormonal Therapy, Standard Dose Chemotherapy, and High
Dose Chemotherapy
Study
Sample size
Median age (yrs)
Rx
SAR (months)
3 yr SAR (%)
5 yr SAR (%)
Reference
San Antonio
New Zealand
POA
E2181
MDACC
ABMTR
HODB
1015
141
250
501
1581
3398
407
58
53–57
57
55
51.7
44
65
Not recorded
SDCT
SDCT
SDCT
SDCT
HDCT
SDCT and HT
23
10–12
14.8
20.9
19
19
20.1
—
9.0
20.0
30.0
28.0
30.0
30.0
—
—
—
18.0
12.2
10.0
17.0
4
60
59
58
16–17
25
—
Rx: treatment after recurrence; SAR: median survival after recurrence; 3 yr SAR: 3-year survival after recurrence; 5 yr SAR: 5-year survival after recurrence; POA: Piedmont Oncology Association; E2181: Eastern
Cooperative Oncology Group E2181; MDACC: M.D. Anderson Cancer Center; ABMTR: Autologous Blood and Marrow Transplant Registry; HODB: Hematology/Oncology Clinic; SDCT: standard dose chemotherapy;
HDCT: high dose chemotherapy; HT: hormonal therapy.
Compared with most clinical trials, treatment in
our clinic was conservative; however, herein is a second flaw: Large numbers of disease recurrences were
treated in other clinics, and it has been difficult to
obtain accurate treatment-related information from
outside offices. We are unable to classify the responses
to MBC treatment for 135 patients (33%). However,
given the fact that the median SAR for this group is
18.1 months, which is only slightly lower than the
median SAR for the entire group, it is doubtful that the
details of their treatment would have altered our final
conclusions substantially. It also should be noted that
our main outcome measure was survival time and not
response to therapy.32 Survival-related information
was 100% complete even for those patients with incomplete treatment records. As of the date of study
closure (December 1998), no one is lost to follow-up
with regard to vital status and/or cause of death if
deceased. Thus, if therapy is considered to be an integral part of the disease process, then OS and SAR can
be calculated without knowledge of treatment response.4,49
Although it is difficult to compare our series of
consecutive cases with other study groups, it actually
is difficult to compare most breast cancer data bases.
For other data bases, because, without an accepted
comprehensive prognostic index,50 –52 we risk comparing “apples with oranges.” Different study groups simply are incommensurable.53 Conventional-dose and
high dose chemotherapy data bases are not only different from one another; but also, and perhaps more
importantly, neither is representative of the general
medical community.5,6,16,17,21,25–29
For example, patient age is a major risk factor of
breast carcinoma. Projected over a life span of 851
years, the risk of developing breast carcinoma is 12.8%
or 1 in 8 women.54 –56 Typical breast carcinoma patients have a median age of 60 – 64 years, similar to our
data base. However, ,2% of breast carcinoma patients
age . 60 years participate in clinical trials.57 Likewise,
the Autologous Blood and Marrow Transplant Registry
(ABMTR) reports a median age of 44 years for MBC
patients25 compared with 65 years in our clinic.
Notwithstanding the obvious barriers to comparisons, it appears nonetheless that our clinic patients
comprised a very poor prognostic cohort. Six of our
patients actually died on the first day of disease recurrence; these patients surely would not have been included in most clinical studies. Thus, perhaps it is not
surprising that our patients faired poorly: A greater
wonder is that their outcome was similar to studies
with more aggressive treatment philosophies. Although clinical end points were not standardized and
outcome measures differed from study to study, a few
examples illustrate the point (Table 5). Despite a wide
range of median ages and various therapies, HODB
median SAR compares favorably with all standarddose chemotherapy trials as well as with ABMTR results with high dose chemotherapy and autotransplants.4,16,17,25,58 – 60
When discussing breast carcinoma patient outcome, there is an additional sobering fact: Untreated
breast carcinoma patients and even untreated MBC
patients can survive for 5–10 years.33,61– 63 Consider
Bloom et al.’s account of the Middlesex Cancer Charity Ward.33 Founded in England in 1745, the Middlesex
Hospital opened a Cancer Charity Ward in 1792 as an
asylum for the terminally ill. From 1747 to 1903, there
were 5526 women with carcinoma, including 1950
(35%) with “malignant disease of the breast.” Bloom et
al. located the clinical records of 356 untreated breast
carcinoma patients. He reported on 250 of these patients with necropsy confirmation of breast carcinoma. The median ages were 51– 60 years, 23% had
locally advanced disease, and 74% had systemic metastases. Patients were treated with opiates, dressings,
Metastatic Breast Carcinoma/Anderson et al.
lead sera, Coley toxin, and thymic extract. None had
surgery, radiotherapy, or hormonal therapy. The median survival was 2.7 years (range, 2 months to 18
years). The 5-year and 10-year overall survival rates
were 18% and 4%, respectively, respectable results for
most clinical trials. All patients were followed to death;
95% experienced a breast carcinoma death, and 5%
died of an intervening illness. There were no spontaneous remissions.
CONCLUSIONS
In summary, although MBC usually is fatal, a number
of patients can survive with and without treatment. A
great mystery of contemporary medical oncology is
that survival times are similar for dissimilar treatments.64 Most MBC patients will respond to standard
cytotoxic systemic chemotherapy, but the majority of
responses are temporary and partial. Proponents of
chemotherapy argue that conventional-dose chemotherapy is not enough and that dose intensification
will be the answer. However, uncontrolled studies of
high dose chemotherapy with autotransplants65 have
not been validated in randomized clinical trials.29,66,67
It may be wise to recognize that dose intensification
could be the medical equivalent of past surgical excesses:24 More treatment may not be better treatment.68 For the past 100 years, there has been little
gain in survival time for patients with MBC. Sadly, and
despite our best efforts, many patients with advanced
breast carcinoma have outcomes similar to untreated
historic controls.69,70 In addition, the widespread use
of adjuvant chemotherapy may complicate further future MBC clinical trials by selecting a drug-resistant
subpopulation.
However, It would be a disservice to the medical
profession and to MBC patients alike if our comments
were viewed as nihilistic and/or were interpreted to
endorse no treatment. We recognize the benefit of a
therapeutic response. In our data base as well as others, patient response to MBC treatment was associated with prolonged SAR (P , 0.001). Along with prolonging survival, treatment also can improve the
quality of life.
Treatment is a reality for most MBC patients;
however, there is a real dilemma in deciding which
protocol to use. We acknowledge the inherent slowness of translational research;71 however, patient
selection bias and incomplete control data prevent
unconditional extrapolations from contemporary
clinical trials to the general medical community.
Given the retrospective nature of our data and other
potentially confounding variables, we also cannot
draw any definite conclusions regarding the benefits
of a specific drug regimen. However, for a disease
105
that most patients will not survive, it seems reasonable to be practical and truthful.72,73 MBC treatment
should achieve maximum palliation and prolong
survival time with limited toxicity.74 For example,
front-line antihormonal therapy for older women
with nonlife-threatening MBC will not jeopardize
survival even for estrogen receptor negative disease.13 Similarly, in our clinic, a conservatively administered community standard of care did not
compromise survival time and/or breast carcinoma
specific mortality. Future progress awaits the development of new chemotherapeutic agents (possibly
taxanes) and/or the emergence of treatment strategies resulting from a better knowledge of molecular
carcinogenesis.
REFERENCES
1.
Chu KC, Tarone RE, Kessler LG, Ries LA, Hankey BF, Miller
BA,et al. Recent trends In U. S. breast cancer incidence,
survival, and mortality rates. J Natl Cancer Inst 1996;88(21):
1571–9.
2. Early Breast Cancer Trialist’s Collaborative Group. Systemic
treatment of early breast cancer by hormonal, cytotoxic, or
immune therapy. 133 randomized trials involving 31,000
recurrences and 24,000 death among 75,000 women. Lancet
1992;339:1–15,71– 85.
3. Bearman SI, Shpall EJ, Jones RB, Cagnoni PJ, Ross M. Highdose chemotherapy with autologous hematopoietic progenitor cell support for metastatic and high-risk primary breast
cancer. Semin Oncol 1996;23(Suppl 2):60 –7.
4. Clark GM, Sledge GW, Osborne CK, McGuire WL. Survival
from first recurrence: relative importance of prognostic factors in 1,015 breast cancer patients. J Clin Oncol 1987;5(1):
55– 61.
5. Ayash LJ, Wheeler C, Fairclough D, Schwartz G, Reich E,
Warren D, et al. Prognostic factors for prolonged progression-free survival with high-dose chemotherapy with autologous stem-cell support for advance breast cancer. J Clin
Oncol 1995;13(8):2043–9.
6. Rahman ZU, Frye DK, Buzdar AU, Smith TL, Asmar L,
Champlin RE, et al. Impact of selection process on response
rate and long-term survival of potential high-dose chemotherapy candidates treated with standard-dose doxorubicincontaining chemotherapy in patients with metastatic breast
cancer. J Clin Oncol 1997;15(10):3171–7.
7. Rosen PP, Groshen S, Saigo PE, Kinne DW, Hellman S.
Pathological prognostic factors in Stage I (T1N0M0) and
Stage II (T1N1M0) breast carcinoma: a study of 644 patients
with median follow-up of 18 years. J Clin Oncol 1989;7(9):
1239 –51.
8. Seidman AD. Chemotherapy for advanced breast cancer: a
current perspective. Semin Oncol 1996;23(Suppl 2):55–9.
9. Falkson G, Gelman RS, Pandya KJ, Osborne CK, Tormey D,
Cummings FJ, et al. Eastern Cooperative Oncology Group
randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete
remission following induction treatment. J Clin Oncol 1998;
16:1669 –76.
10. Schapira DV, Urban N. A minimalist policy for breast cancer
surveillance. JAMA 1991;265(3):380 –2.
106
CANCER January 1, 2000 / Volume 88 / Number 1
11. Norton L. Metastatic breast cancer length and quality of life.
N Engl J Med 1991;325:1370 –1.
12. Fisher B, Osborne CK, Margolese R, Bloomer W. Treatment
of metastatic breast cancer. In: Holland JF, Frei EI, Bast RC,
Kufe DW, Morton DL, Weichselbaum RR, editors. Cancer
medicine, 3rd ed. Philadelphia: Lea & Febiger, 1993:1719.
13. Muss HB. The role of chemotherapy and adjuvant therapy in
the management of breast cancer in older women. Cancer
1994;74(7 Suppl):2165–71.
14. Budman DR, Berry DA, Cirrincione CT, Henderson IC,
Wood WC, Weiss RB, et al. Dose and dose intensity as
determinants of outcome in the adjuvant treatment of
breast cancer. J Natl Cancer Inst 1998;90:1205–11.
15. Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J,
Hart RD, et al. Dose and dose intensity of adjuvant chemotherapy for Stage II, node-positive breast carcinoma. N Engl
J Med 1994;330:1253–59.
16. Greenberg PAC, Hortobagyi GN, Smith TL, Ziegler LD, Frye
DK, Buzdar AU. Long-term follow-up of patients with complete remission following combination chemotherapy for
metastatic breast cancer. J Clin Oncol 1996;14(8):2197–205.
17. Rahman ZU, Frye DK, Smith TL, Asmar L, Theriault RL,
Buzdar AU, et al. Results and long term follow-up for 1581
patients with metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy. Cancer
1999;85:104 –11.
18. Norton L. Evolving concepts in the systemic drug therapy of
breast cancer. Semin Oncol 1997;24(4)(Suppl 10):S10-3–10.
19. Hudis CA, Norton L. Adjuvant drug therapy for operable
breast cancer. Semin Oncol 1996;23(4):475–93.
20. Hudis CA, Norton L. Adjuvant drug treatment for resectable
breast cancer. Oncologist 1997;2:351– 8.
21. Sledge GW. Should we dream the impossible dream? The
meaning of long-term survival in metastatic breast cancer.
J Clin Oncol 1996;14(8):2191–3.
22. General Accounting Office. Breast cancer patients’ survival.
Washington, DC: General Accounting Office of the United
States, 1989.
23. Mueller CB. The case against the use of adjuvant chemotherapy in breast cancer. Bull Am Coll Surg 1993;78:25–31.
24. Editorial. Breast cancer: have we lost our way? Lancet 1993;
341:343– 4.
25. Antman KH, Rowlings PA, Vaughan WP, Pelz CJ, Fay JW,
Fields KK, et al. High-dose chemotherapy with autologous
hematopoietic stem-cell support for breast cancer in North
America. J Clin Oncol 1997;15(5):1870 –9.
26. Crump M, Goss PE, Prince M, Girouard C. Outcome of
extensive evaluation before adjuvant therapy in women with
breast cancer and 10 or more positive axillary lymph nodes.
J Clin Oncol 1996;14(1):66 –9.
27. Canellos GP. Selection bias in trials of transplantation for
metastatic breast cancer: have we picked the apple before it
was ripe? J Clin Oncol 1997;15(10):3169 –70.
28. Garcia-Carbonero R, Hidalgo M, Paz-Ares L, Calzas J, Gomez
H, Guerra JA, et al. Patient selection in high-dose chemotherapy trials: relevance in high-risk breast cancer. J Clin
Oncol 1997;15(10):3178 – 84.
29. Savarese DMF, Hsieh C-C, Stewart FM. Clinical impact of
chemotherapy dose escalation in patients with hematologic
malignancies and solid tumors. J Clin Oncol 1997;15(8):
2981–95.
30. LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian
F. Discrepancies between meta-analyses and subsequent
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
large randomized, controlled trials. N Engl J Med
1997;337(8):536 – 42.
Byar DP. Why data bases should not replace randomized
clinical trials. Biometrics 1980;36:336 – 42.
A’Hern RP, Ebbs SR, Baum MB. Does chemotherapy improve survival in advanced breast cancer? A statistical overview. Br J Cancer 1988;57(6):615– 8.
Bloom HJG, Richardson WW, Harries EJ. Natural history of
untreated breast cancer (1805–1933). Br Med J 1962;2:213–
21.
Diehl LF, Perry DJ. A comparison of randomized concurrent
control groups with matched historical control groups: are
historical controls valid? J Clin Oncol 1986;4(7):1114 –20.
Debonis D, Terz JJ, Eldar S, Hill LR. Survival of patients with
metastatic breast cancer diagnosed between 1955 and 1980.
J Surg Oncol 1991;48(3):158 – 63.
Hayward JL, Carbone PP, Heuson J-C, Kumaoka S, Segaloff
A, Rubens RD. Assessment of response to therapy in advanced breast cancer. Cancer 1977;39(3):1289 –94.
Fleming ID, Cooper JS, Henson DE, Hutter RVP, Kennedy BJ,
Murphy GP, et al. Breast AJCC cancer staging manual, 5th
ed. Philadelphia: Lippincott-Raven, 1997:171– 80.
StatSoft, Inc. Statistica for Windows, version 5.1. Tulsa, OK:
Statsoft, Inc., 1998.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 81.
Peto R, Peto J. Asymptomatically efficient rank invariant test
procedures. J R Stat Soc 1972;135(A):18598.
Cox DR. Regression models and life-tables. J R Stat Soc
1972;34(B):187–220.
Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic
research: principles and quantitative methods. New York:
John Wiley & Sons, 1982.
Simpson JF, Page DL. Status of breast cancer prognostication based on histopathologic data. Am J Clin Pathol 1994;
102(Suppl 1):S3– 8.
Saphner T, Tormey DC, Gray R. Annual hazard rates of
recurrence for breast cancer after primary therapy. J Clin
Oncol 1996;14(10):2738 – 46.
Rubens RD, Bajetta E, Bonneterre J, Klijn JG,Lonning PE,,
Paridaens R. Treatment of relapse of breast cancer after
adjuvant systemic therapy-review and guidelines for future
research. Eur J Cancer 1994;30A(1):106 –11.
Bonneterre J, Mercier M. Response to chemotherapy after
relapse in patients with or without previous adjuvant chemotherapy for breast cancer. Cancer Treat Rev 1993;
19(Suppl B):21–30.
Ahmann FR, Jones SE, Moon TE. The effect of prior adjuvant
chemotherapy on survival in metastatic breast cancer. J Surg
Oncol 1988;37(2):116 –22.
Moses LE. The series of consecutive cases as a device for
assessing outcomes of interventions. In: Bailar JC, Mosteller
F, editors. Medical uses of statistics, 2nd ed. Boston: New
England Journal of Medicine Books, 1992:125– 40.
Mueller CB, Jefferies W. Cancer of the breast: its outcome as
measured by the rate of dying and causes of death. Ann Surg
1975;182:334 – 41.
Black WC, Welch HG. Advances in diagnostic imaging and
overestimation of disease prevalence and the benefits of
therapy. N Engl J Med 1993;328(17):1237– 43.
Shipp MA. A predictive model for aggressive non-Hodgkin’s
lymphoma. N Engl J Med 1993;329(14):987–94.
Metastatic Breast Carcinoma/Anderson et al.
52. Yamamoto N, Watanabe T, Katsumata N, Omuro Y, Ando M,
Fukuda H, et al. Construction and validation of a practical
prognostic index for patients with metastatic breast cancer.
J Clin Oncol 1998;16: 2401– 8.
53. Bailar JC. Diagnostic drift in the reporting of cancer incidence. J Natl Cancer Inst 1998;90(11):863– 4.
54. Editorial. Assessing the odds [editorial]. Lancet 1998;350:
1563.
55. Feuer EJ, Wun LM, Boring CC, Flanders WD, Timmel MJ,
Tong T. The lifetime risk of developing breast cancer. J Natl
Cancer Inst 1993;85(11):892–7.
56. Phillips K-A, Glendon G, Knight JA. Putting the risk of breast
cancer in perspective. N Engl J Med 1999;340(2):141– 4.
57. American College of Physicians. Oncology medical knowledge self-assessment program. Philadelphia: American College of Physicians, 1999.
58. Falkson G, Gelman R, Falkson CI, Glick J, Harris J. Factors
predicting for response, time to treatment failure, and survival in women with metastatic breast cancer treated with
DAVTH: a prospective Eastern Cooperative Oncology Group
study. J Clin Oncol 1991;9(12):2153– 61.
59. Muss HB, Case LD, Richards F II, White DR, Cooper MR,
Cruz JM, et al. Interrupted versus continuous chemotherapy
in patients with metastatic breast cancer. The Piedmont
Oncology Association [see comments]. N Engl J Med 1991;
325(19):1342– 8.
60. Perez DJ, Harvey VJ, Robinson BA, Atkinson CH, Dady PJ,
Kirk AR, et al. A randomized comparison of single-agent
doxorubicin and epirubicin as first-line cytotoxic therapy
in advanced breast cancer. J Clin Oncol 1991;9(12):2148 –
52.
61. Daland EM. Untreated cancer of the breast. Surg Gynecol
Obstet 1927;44:264 – 8.
62. Greenwood M. A report On the natural duration of cancer.
Rep Public Health Med Subj HMSO 1926;33:1–26.
63. Nathanson IT, Welch CE. Life expectancy and incidence of
malignant disease. I. Carcinoma of the breast. Am J Cancer
1936;28:40 –53.
107
64. Norton L. Kinetic concepts in the treatment of breast cancer. Recent Results Cancer Res 1993;127:1– 6.
65. Peters WP, Ross M, Vredenburgh JJ, Meisenberg B, Marks
LB, Winer E, et al. High-dose chemotherapy and autologous
bone marrow support as consolidation after standard-dose
adjuvant therapy for high-risk primary breast cancer. J Clin
Oncol 1993;11(6):1132– 43.
66. Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, Baars
JW, Koning CC,et al. Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement [see comments]. Lancet 1998;352(9127):515–21.
67. Stadtmauer EA, O’Neill A, Goldstein LJ, et al. Phase III randomized trial of high-dose chemotherapy (HDC) and stem
cell support (SCT) shows no difference in overall survival or
severe toxicity compared to maintenance chemotherapy
with cyclophosphamide, methotrexate and 5-fluorouracil
(CMF) for women with metastatic breast cancer who are
responding to conventional induction chemotherapy: the
“Philadelphia” Intergroup Study (PBT-1). Proc Am Soc Clin
Oncol 1999;18:1a.
68. Hudis CA, Munster PN. High-dose therapy for breast cancer.
Semin Oncol 1999;26:35– 47.
69. Gardner B, Feldman J. Are positive axillary nodes in breast
cancer markers for incurable disease? Ann Surg 1993;218(3):
270 – 8.
70. Fox MS. On the diagnosis and treatment of breast cancer.
JAMA 1979;241(5):489 –94.
71. Cannistra SA. “Cancer defeated”: not if, but when—introducing the Biology of Neoplasia Series. J Clin Oncol 1997;
15(11):3297– 8.
72. Smith TJ. Knowing when to bow out gracefully. In: Oncology
News International, vol 5. New York: 1996:1,22.
73. Smith TJ, Swisher K. Telling the truth about terminal cancer.
JAMA 1998;279(21):1746 – 8.
74. Hortobagyi GN. Treatment of breast cancer. N Engl J Med
1998;339(14):974 – 84.
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