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A Role for Curative Surgery in the Treatment of Selected
Patients with Metastatic Breast Cancer
S. EVA SINGLETARY,a GARRETT WALSH,b JEAN-NICOLAS VAUTHEY,a STEVEN CURLEY,a
RAYMOND SAWAYA,c KRISTIN L. WEBER,a FUNDA MERIC,a GABRIEL N. HORTOBÁGYId
Departments of aSurgical Oncology, bThoracic and Cardiovascular Surgery, cNeurosurgery, and dBreast
Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
Key Words. Breast cancer · Metastasis · Surgery · Median survival
L EARNING O BJECTIVES
After completing this course, the reader will be able to:
1. Explain how surgery in combination with systemic therapy may offer significantly improved survival outcomes in
selected patients with metastatic breast cancer.
2. Appreciate the value of chest x-rays in follow-up to identify patients with pulmonary or sternal metastases who may
be candidates for surgical resection.
3. Recognize that the concept of a “cure” in breast cancer is evolving to mean a prolonged period of survival without
significant symptoms.
CME
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
A BSTRACT
Although metastatic breast cancer is widely believed
to carry a grim prognosis, treatment developments over
the past 25 years have greatly improved survival outcomes in these patients. In selected cases, aggressive
treatment approaches may occasionally result in longterm survival of 15 years or more. This review considers
the role of surgery in the treatment of single or multiple
metastatic lesions restricted to one site. For each site,
available literature from 1992-2002 was assessed to determine the role of surgery on survival outcomes and to
determine appropriate criteria for selecting the best candidates for surgery. For lung, liver, brain, and sternum
metastases, the use of surgery with or without adjuvant
therapy resulted in greater median survival times and
5-year survival rates. The best candidate for surgery had
no evidence of additional metastatic disease, good performance status, and a long disease-free interval after treatment of the primary tumor. Current treatment standards
for breast cancer follow-up do not include imaging studies other than mammography. The addition of chest
x-rays as part of routine follow-up should be considered
as a cost-effective approach for early assessment of metastases to the lung or sternum that may be appropriate for
surgical excision. The Oncologist 2003;8:241-251
INTRODUCTION
The traditional belief of both patients and their physicians has been that metastatic breast cancer offers only the
grimmest prognosis, with average survival times of 1-2
years. This belief has fostered treatment regimens based on
the notion that palliative treatment is the optimal choice for
Correspondence: S. Eva Singletary, M.D., FACS, Department of Surgical Oncology, The University of Texas M.D. Anderson
Cancer Center, 1515 Holcombe Boulevard, Box 444, Houston, Texas 77030-4095, USA. Telephone: 713-792-6937; Fax: 713792-2225; e-mail: [email protected] Received January 15, 2003; accepted for publication April 8, 2003. ©AlphaMed
Press 1083-7159/2003/$12.00/0
The Oncologist 2003;8:241-251 www.TheOncologist.com
242
most patients, with more aggressive therapeutic approaches
likely to result in useless patient distress.
It is certainly true that, in the absence of intercurrent
causes of death, most patients who develop breast cancer
metastases ultimately die of their disease, with an overall
survival rate of approximately 2% at 20 years after diagnosis with metastases [1]. It is equally true, however, that new
treatment modalities developed over the past 25 years have
resulted in significantly improved median survival times for
patients with metastatic disease. A recent study by Giordano
and colleagues [2] examined outcomes in 1,986 breast cancer patients who received similar treatment for their primary
disease at a single institution between the years of 1974 and
2000. Of the original patient sample, 843 developed recurrent disease. Those patients who were diagnosed with recurrent disease in the interval from 1974-1979 had a median
survival of 15 months, with 3- and 5-year overall survival
rates of 15% and 10%, respectively. Patient outcomes
improved steadily over the following 20 years, with patients
diagnosed with recurrent disease in the interval from 19952000 showing a median survival of 51 months, and 3- and
5-year overall survival rates of 61% and 40%, respectively.
With these longer median survival times, the treatment
paradigm for metastatic breast cancer is evolving. A recent
paper by O’Shaughnessy [3] outlines a clinical strategy
based on prolonged tumor control with minimal toxicity.
For patients who have no significant symptoms and who
respond to first-line therapy (typically hormonal for
patients whose metastatic disease is estrogen-receptor or
progesterone-receptor positive), such a strategy can result
in long progression-free intervals and postponement of the
need for more toxic therapies.
A more aggressive treatment approach may be appropriate for those patients in whom metastatic disease is limited to a solitary lesion or to multiple lesions at a single
organ site. When those patients can be rendered clinically
disease free by local treatment (surgery or radiation), there
is the potential of achieving a complete remission from
chemotherapy, and patients can remain disease free for prolonged periods of time (15-20 years or more). In a clinical
trial conducted at the M.D. Anderson Cancer Center by
Holmes and colleagues [4], patients with solitary metastases
were treated with surgical resection with or without radiation therapy, followed by systemic chemotherapy, consisting of fluorouracil, doxorubicin, and cyclophosphamide,
and hormonal therapy, consisting of tamoxifen. Nearly 25%
of patients were alive without disease 15 years after treatment, and only two additional events occurred at a maximum follow-up of 26 years [4, 5]. Related reports from
Borner and colleagues [6] and from Nieto and colleagues [7]
provide additional evidence that an aggressive multimodal
Surgery and Metastatic Breast Cancer
therapy can significantly increase disease-free survival in
selected patients with limited metastastic disease.
Breast cancer metastases isolated to a single organ commonly occur in lung, liver, brain, and bone. This review article considers the role of surgery with or without adjuvant
therapy in the treatment of single or multiple metastatic lesions
restricted to one of these specific sites. For each site, available
literature from 1992-2002 was assessed to determine the role
of surgery on survival outcomes and to determine appropriate
criteria for selecting the best candidates for surgery.
SITES OF BREAST CANCER METASTASIS
Lung
Approximately 3% of all women with breast cancer
develop a solitary pulmonary lesion detectable by chest x-ray,
of which 33%-40% will be breast metastases [8, 9]. Lung
resection for metastatic disease was first reported in 1882 by
Weinlechner [10] and, in 1939, Churchill performed the first
resection of a pulmonary metastasis leading to long-term survival [11]. Since that time, surgery has become a standard
treatment in patients with solitary pulmonary metastases, with
5-year survival rates of approximately 35%, depending on the
primary site [12].
Table 1 presents the results of eight retrospective studies
that examined survival outcomes in breast cancer patients
with isolated metastases to the lung treated with surgery with
or without postsurgical systemic therapy [9, 13-19]. Median
survival times ranged from 42 months to 79 months, with 5year actuarial survival rates ranging from 35%-80% and 10year actuarial survival rates ranging from 8%-60%. In two
studies that presented outcomes from patients who received
medical treatment only (usually chemotherapy) for pulmonary metastases [15, 18], survival was significantly lower
for those patients. In a study by Staren and coworkers [15],
the mean survival time was 55 months in the group receiving
surgery compared with 33 months in the group receiving
medical treatment only. Murabito and colleagues [18]
reported a mean survival time of 79 months in patients receiving surgery versus 9 months in patients receiving medical
treatment only. Across all eight studies, there was no apparent
survival advantage related to treatment with postsurgical systemic therapy in addition to surgery, but precise data bearing
on this issue were not available from many of these studies.
Positive survival outcomes after surgery, with or without
chemotherapy, were associated with a long disease-free
interval (DFI) after treatment of the primary tumor (12-36
months) [14, 16, 19], with complete resection of the tumor
[9, 17, 19], and with estrogen-receptor-positive status [14]. In
the largest study in that series (n = 467) [19], the best candidates (DFI greater than 36 months and complete resection)
Singletary, Walsh, Vauthey et al.
243
Table 1. Survival outcomes in breast cancer patients with isolated metastases to the lung treated with surgery with or without chemotherapy
Survival
Study
n of patients
Ishida et al. [13]
Lanza et al. [14]
4
37
Staren et al. [15]
McDonald et al. [9]
33
60
Simpson et al. [16]
17
Livartowski et al. [17]
Murabito et al. [18]
Friedel et al. [19]
40
86
467
Treatment
Median (months)
5-year (%)
10-year (%)
NS
47
75
50
NS
NS
55a
42
35
38
NS
8
NS
62
NS
70
79a, c
50d
54
80c
45d
NS
60c
26d
Surgery
Surgery + chemotherapy with or
without tamoxifen
Surgery
Surgery alone (n = 17) or with
chemotherapy (n = 43)
Surgery alone (n = 2) or with
chemotherapy (n = 15)
Surgery
Surgery + chemotherapyb
Surgery alone (n = 308) or with
chemotherapy (n = 159)
a
Mean values
Percentage of patients receiving chemotherapy not specified
c
Survival outcomes associated with complete resection of metastatic lesion
d
Survival outcomes associated with a DFI > 36 months before detection of metastatic lesion
NS = not specified
b
had a 5-year survival rate of 50% and a 15-year survival rate
of 25% after surgery, with or without chemotherapy, indicating that this treatment approach is curative in this select
group of patients.
Even without the potential survival benefit associated
with surgical resection of metastases, there is an obvious
additional reason for recommending at least limited surgery
for breast cancer patients with isolated pulmonary lesions.
As indicated above [8, 9], only about one-third of such
lesions will prove to be breast cancer metastases, while the
remaining two-thirds will be other types of tumors, chiefly
primary lung cancer. Early identification of the tumor is
critical for determining appropriate treatment strategies.
Liver
More than half of all patients with metastatic breast
cancer will have liver involvement at some point [20].
Typically, this is a late finding, when metastases are already
present at other sites. Those patients with obvious multisite
liver disease are usually treated with systemic therapy,
although intra-arterial regional chemotherapy may be used
for treatment of multiple liver metastases.
Of all patients with metastatic breast cancer, approximately 5% will have metastasis confined to the liver with no
evidence of extrahepatic disease [21, 22]. Even with systemic
chemotherapy, the median survival time for patients with
metastatic disease to the liver only or with limited disease elsewhere is only 19 months, with pretaxane chemotherapy regimens, or 22-26 months with taxane-containing regimens [23].
Hormonal therapy is of limited use, as most breast tumors that
metastasize to the liver are hormone-receptor negative [24].
Because of the lack of effective systemic therapy, surgery has
been proposed as a potential therapeutic tool for increasing
survival in patients with isolated hepatic metastases.
Only a small number of retrospective studies have
examined outcomes in breast cancer patients with isolated
hepatic metastases treated with surgery, and the patient
numbers in those studies are relatively small. Nonetheless,
there is evidence that the use of surgery with or without
chemotherapy in treating these patients can significantly
increase survival. As shown in Table 2, the median survival
times in six published studies ranged from 24-44 months,
and the 5-year survival rates ranged from 22%-38%, with
one study showing a 4-year survival rate of 46% [25-30]. In
a study by Selzner and coworkers [28], 4 of 17 patients were
alive without evidence of disease at 6 months, 17 months,
6 years, and 12 years after surgery.
In unpublished data from the University of Texas M.D.
Anderson Cancer Center, 21 patients underwent resection
and/or radiofrequency ablation with curative intent for isolated liver metastases between January 1987 and July 2000.
Liver metastases developed after a median time of 35
months (range 0-144) from initial diagnosis. Fourteen
patients had a solitary metastasis and seven had two lesions.
The vast majority (81%) of patients received adjuvant
chemotherapy for the primary tumor or neoadjuvant
chemotherapy for the liver recurrence. The type of surgery
included major hepatectomy (resection of one or more
Surgery and Metastatic Breast Cancer
244
Table 2. Survival outcomes in breast cancer patients with isolated metastases to the liver treated with surgery with or without chemotherapy
Survival
Study
Schneebaum et al. [25]
Raab et al. [26]
n of patients
6
35b
Treatment
a
Median (months)
5-year (%)
10-year (%)
Surgery + regional chemotherapy
42
NS
NS
Surgery alone (n = 32) or with
regional chemotherapy (n = 2)
42c
22
NS
Santoro et al. [27]
15
Surgery + chemotherapy
44
38
NS
Selzner et al. [28]
17
Surgery + high-dose chemotherapy
24
22
NS
Yoshimoto et al. [29]
17
Surgery + chemotherapy (systemic
or regional)
34
30
NS
Pocard et al. [30]
65
Surgery + chemotherapy
NS
46d
NS
a
Regional chemotherapy = intra-arterial chemotherapy via the hepatic artery
b
Solitary metastasis in 59% (n = 21) of patients
c
Survival outcomes shown are for patients receiving complete resection; patients receiving palliative surgery had a median survival time of 5 months
and a 5-year survival rate of 0%
c
d
Survival at 4 years
NS = not specified
lobes) in seven patients, minor hepatectomy in nine
patients, and radiofrequency ablation alone or in combination with resection in five patients. There were no perioperative mortalities. The median disease-free survival time
was 40 months, and the disease-free 3-year survival rate
was 55%. These survival results are comparable with those
reported in the literature (Table 2). The role of radiofrequency ablation should be further evaluated in larger subsets of patients. At this time, it should be reserved for
patients who cannot undergo safe resection or used as an
adjuvant to resection.
Perhaps because of the small numbers of patients for
whom data are available, there is also a limited amount of
data about prognostic factors for increased survival after
surgery in breast cancer patients with isolated hepatic
metastases. Most would agree that the patient should show
normal performance status and normal liver function tests.
Two studies agreed that the size and number of hepatic
metastases did not influence survival, but disagreed about
whether the interval between treatment of the primary
tumor and detection of the metastasis was an important factor [28, 30]. Selzner and colleagues did not find an effect on
survival based on extent of liver resection [28]. Raab and
colleagues reported a significant effect related to achieving
a margin-negative resection of all metastatic liver lesions,
with a median survival time of 42 months in patients receiving complete resection compared with 5 months in patients
receiving palliative surgery [26]. Of special interest, two
studies reported that the presence of extrahepatic metastases did not affect survival in patients in whom hepatic
metastases had been surgically removed [28, 30]. This may
be because, with the exception of brain lesions, metastases
at other sites tend to develop more slowly, and the hepatic
metastasis is the rate-limiting factor for patient survival.
Brain
Brain metastases are diagnosed in approximately 10%
of breast cancer patients [31]. Without treatment, the median
survival for these patients is a mere 1-2 months [32-34].
With whole brain radiation therapy (WBRT), this figure
increases to 3-6 months [33-36]. Brain lesions typically
involve obvious and frightening neurological symptoms,
and treatment has historically been aimed at the rapid palliation of these symptoms using WBRT and steroids. While
this treatment approach is effective in most patients over the
short term, symptoms usually return within 2-3 months [37].
In up to one-third of breast cancer patients with brain
metastases, the brain is the only site of metastasis [33, 38,
39]. For those patients, depending upon the size and location
of their lesions, surgical excision added to WBRT can significantly increase survival. In the five studies shown in
Table 3 [31, 40-44], the median survival time for the combination of surgery and WBRT ranged from 15 to 37
months, with 5-year survival rates of 7%, 17%, 20%, and
38% reported in four studies [40-44]. The largest study in
that series (n = 70) reported a median survival time of 15
months and a 5-year survival rate of 7% [43]. It should be
noted that the 38% 5-year survival rate and a subsequent 20%
10-year survival rate were reported in a study with a very
small sample size (n = 8) [41]. Nonetheless, it does point out
the possibility of prolonged survival following surgical excision and radiotherapy for isolated brain metastases. This is
Singletary, Walsh, Vauthey et al.
245
Table 3. Survival outcomes in breast cancer patients with isolated metastases to the brain treated with surgery with or without WBRT
Survival
Study
n of patients
Median (months)
5-year (%)
10-year (%)
9
25
Surgery alone
Surgery + WBRT
15a
28a
NS
20b
NS
Kocher et al. [41]
8
Surgery + WBRT
37
38
20
Boogerd et al. [31]
28
Surgery with or without WBRT
with or without chemotherapy
23
NS
NS
Pieper et al. [42]
63
Surgery with or without WBRT
with or without chemotherapy
16
17
NS
Wronski et al. [43]
70
Surgery alone (n = 9) or with
WBRT (n = 61)c
15c
7
NS
Fokstuen et al. [44]
10
Surgery + WBRT
21a
NS
NS
Salvati et al. [40]
Treatment
a
Figures are mean survival times
b
Survival rate at > 3 years
c
n = 15 patients received WBRT before surgery
NS = not specified
also illustrated in a case report by Nieder and colleagues of
a 51-year-old woman with a solitary brain metastasis presenting 11 months after treatment for stage II node-negative
breast carcinoma [45]. She was treated with surgical excision and WBRT, followed by long-term tamoxifen treatment. At the time of the report, she was alive with no
evidence of disease more than 10 years after diagnosis of the
brain metastasis.
The presence of leptomeningeal disease is a very poor
prognostic sign and contraindicates surgical excision of
brain metastases [43]. Patients are generally considered good
candidates for surgical therapy if they have a single, operable brain lesion and well-controlled systemic disease.
However, a study by Wronski and colleagues [43] did not
find any significant differences in outcomes among patients
with single or multiple brain metastases or patients who had
concurrent lung metastases. They also did not find any difference in outcome related to the interval between diagnosis
of the primary tumor and diagnosis of the metastasis, but two
other studies [40, 41] did report longer survival associated
with a longer DFI.
Over the past 10 years, there has been increasing interest in the use of single-fraction stereotactically delivered
radiation therapy (commonly called sterotactic radiosurgery or SRS) as a substitute for surgical excision in the
treatment of brain metastases. SRS delivers an intense dose
of radiation to a well-defined area within the brain. It has
the advantage of being noninvasive and, because of the
sharp dose gradient used, collateral damage to surrounding
normal tissue is minimized. In three studies that have used
SRS for the treatment of brain metastases of various origin,
median survival times have ranged from 6-8 months, and 1year survival rates have ranged from 38%-44% [46-48].
One study reported a 5-year survival rate of 16% [48].
While these results are an improvement over the use of
WBRT alone, they still lag behind results obtained using a
combination of surgical excision and WBRT. In addition,
larger lesions (>3 cm maximum diameter) may not respond
as well to SRS [43]. Intuitively, treatment of these larger
lesions also carries a higher risk of radiation damage to surrounding normal tissue. At present, the most prudent therapeutic strategy may be to use surgical excision where
possible, reserving SRS for those cases in which the tumor
is located in an inaccessible site or is otherwise inoperable.
Bone
Bone is one of the earliest and most common sites of
breast cancer metastasis. The invasion of cancer cells into
bone initiates a cycle that involves destruction of the bone
(through activation of osteoclasts) and subsequent release
of cellular growth factors leading to increased cancer cell
growth [49]. The typical presenting symptom for bone
metastasis is pain. As bone destruction progresses, fractures
become more likely. In weight-bearing bones, this can lead
to problems of mobility. Spinal cord compression can be an
acute, life-threatening complication.
The usual first treatment choice for bone metastases not at
risk for fracture is systemic therapy, either hormonal therapy
or chemotherapy. This is especially true for isolated lesions,
which account for approximately 20% of all bone metastases
[50]. Isolated bone metastases have a somewhat indolent
course and generally respond well to hormonal therapy
246
[51-53]. For patients in whom the metastases are hormonereceptor negative, or who become refractory to hormonal
treatment, chemotherapy has been shown to be effective [54].
In metastatic disease confined to the skeletal system and
treated with hormonal therapy with or without chemotherapy,
a median survival time of 48 months and a 5-year survival rate
of 39% have been reported [51, 55]. More recently, osteoclast
inhibitory therapy using bisphosphonates has become widely
used [56]. Radiation therapy, either locally or through the systemic administration of radioisotopes, has also been used
effectively in these patients, providing pain relief and, in some
cases, evidence of bone healing [57, 58].
The use of surgery for the treatment of bone metastases
has typically been reserved for lesions that are not responsive to systemic therapy and that are associated with a serious potential for decline in quality of life in order to reduce
fractures, treat spinal cord or nerve compressions, and prophylactically fix imminent fractures. The most common
goals of surgery are to maintain or restore mobility and to
decrease pain, and the most common use is for the treatment of long bone fractures. Surgical treatment of impending or actual long bone fractures is generally performed to
stabilize the bone rather than remove the tumor.
The use of surgery as a curative treatment option for
bone metastases has been actively considered in the case of
isolated metastases to the sternum. Two studies from the
1980s presented results from a limited number of patients
indicating that surgical resection of solitary sternal metastases, where there was no evidence of systemic spread, may
have led to significantly better survival. Takanami and
Ohnishi [59] treated three patients,
each with a single sternal metastaFigure 1. A suspected sternal metastasis in a 69-year-old woman previously
treated for cancer in the right breast.
A) Preoperative photograph showing
sternal lesion protruding from chest
wall (lateral view). B) Computerized
tomography scan of chest wall showing
sternal lesion. C) Removal of specimen.
The underlying right lung was compressed but not invaded; the left lung
was normal. Some of the mediastinal fat
and thymus was removed en bloc with
the tumor. D) Positioning of a free
TRAM flap for reconstruction of the surgical deficit. The base of the reconstruction was a double layer of Marlex®
without methylmethacrylate. The TRAM
flap was attached into the right internal
mammary artery and vein. Photographs
courtesy of Drs. Garrett Walsh and
Pierre Chevray, M.D. Anderson Cancer
Center.
Surgery and Metastatic Breast Cancer
sis from breast cancer, with partial resection of the sternum.
Two patients died within 14 months, but the third was alive
and disease free 7 years after surgery. Noguchi and coworkers [60] treated nine patients with solitary sternal metastases
from breast cancer with either partial (n = 8) or total (n = 1)
resection of the sternum. The median survival time for all
nine patients was 30 months. Of the five patients who had no
mediastinal or parasternal lymph node metastases, three survived more than 6 years. More recently, Incarbone and colleagues reviewed results from their institution from 52
patients who underwent surgical resection for tumors involving the sternum [61]. Of these, 11 involved breast cancer
metastases. These patients showed a 60% 5-year survival rate
and a median survival time described by the authors as
“remarkably long.” Noguchi and colleagues [60] suggested
that resection of sternal metastases may lead to long-term
survival because these lesions remain solitary for a long time,
possibly because of isolation from the venous plexus that
provides a transmission route to other bones.
As shown in Figure 1, current reconstructive techniques
using synthetic mesh in conjunction with autologous tissue
transplants make surgical resection possible even for very
large lesions. The patient shown in Figure 1 was a 69-yearold woman with a prior history of carcinoma in the right
breast that had been treated with segmental mastectomy,
radiation, and chemotherapy. Twenty-seven months later,
she developed a large, rapidly growing sternal lesion that was
a suspected metastasis from the previous breast cancer. The
sternal lesion was refractory to chemotherapy. The surgeon
was able to preserve a portion of the manubrium and to
Singletary, Walsh, Vauthey et al.
247
Table 4. Perioperative morbidity and mortality in patients receiving surgical treatment for metastatic breast cancer
Site of metastasis
Lung
Study
Morbidity (n, %)
Lanza et al. [14]
3/37 (8%)
Prolonged air leaks at thoracotomy site
0/37 (0%)
McDonald et al. [9]
8/60 (13%)
Pneumothorax, pulmonary embolism, atrial
fibrillation, thoracotomy site infection, atelectasis
1/60 (2%)
1/17 (6%)
Cardiovascular accident
0/17 (0%)
Bile leakage, postoperative bleeding, infection
1/35 (3%)
Simpson et al. [16]
Liver
Raab et al. [26]
10/35 (29%)
Type of morbidity
Mortality (n, %)
Santoro et al. [27]
0/15 (0%)
NS
0/15 (0%)
Selzner et al. [28]
0/17 (0%)
NS
1/17 (6%)
NS
NS
0/17 (0%)
Yoshimoto et al. [29]
Pocard et al. [30]
12/65 (18%)
Brain
Pieper et al. [42]
0/63 (0%)
Bone
Incarbone et al. [61]
14/52 (27%)b
Pleural effusions
0/65 (0%)
NS
0/63 (0%)a
Wound necrosis, superficial infection, seroma,
local sepsis, pyrexia
0/11 (0%)b
a
Three patients died within 30 days of surgery from disseminated disease
b
The total study sample included 52 patients with sternal metastases, 11 of whom had metastases from breast cancer; morbidity was not broken down
by disease site
b
NS = not specified
reconstruct the chest wall using a double layer of Marlex®
(Davol; Cranston, RI) without methylmethacrylate and a free
transverse abdominis myocutaneous (TRAM) flap attached
to the right internal mammary artery and vein.
PERIOPERATIVE MORBIDITY AND MORTALITY IN
PATIENTS RECEIVING SURGICAL TREATMENT FOR
METASTATIC BREAST CANCER
Approximately one-half of the reviewed studies
reported perioperative morbidity and mortality (Table 4).
The mortality rates were very low (median 0%, range 0%6%). The morbidity rates varied widely (median 8%, range
0%-29%), but specific types of morbidity were generally
reported as minor.
SOURCES OF BIAS IN INTERPRETING THE VALUE OF
SURGERY
It is important to note that the results shown in these
studies may be influenced by selection bias. It may be
that patients selected for surgery had better prognostic
features than those treated with chemotherapy alone.
Unfortunately, because of the lack of studies that directly
compared outcomes in these two groups, there are few
data that bear directly on this issue. In two lung metastasis studies that compared outcomes in patients receiving
surgery compared with those receiving chemotherapy
[15, 18], there were no significant differences in relevant
patient characteristics including stage, histology, hormone receptor levels of the primary tumor, number of
metastases, and length of DFI. However, these studies did
not report whether there were differences in performance
statuses between the two treatment groups, and this can
be an important predictor of survival. Patients with poor
performance statuses are generally considered to be poor
surgical risks and are often recommended for alternative
nonsurgical therapies. This could introduce an important
source of bias into an assessment of the value of surgery.
Publication bias against series in which there was no
survival benefit may also affect the results presented here.
It might be argued that the relatively small number of cases
reported in these studies (e.g., 744 lung metastases from
breast) is only a fraction of the total cases in which surgery
was used as a treatment option. However, the absolute number of breast metastases that are eligible for resection is
likely to be relatively small. For example, while approximately 1%-1.5% of women with breast cancer develop
metastasis to the lung, only about 25% of those patients
may be recommended for surgery [9]. A review of the M.D.
Anderson Cancer Center database starting in 1984 (most
reliably captured after 1997) revealed only 56 patients who
underwent thoracotomy for breast cancer metastasis to the
lung. Thus, the small number of reported cases is not itself
a reliable indicator of publication bias. It is also important
to note that a 2002 analysis of 467 patients from the
International Registry of Lung Metastases (the single
largest database on metastasis to the lung) showed patient
outcomes consistent with those from smaller studies
reported here. Thus, we do not believe that publication bias
seriously undermined our conclusions about the potential
value of surgery in the treatment of lung metastases.
248
DISCUSSION
The data reviewed here indicate that surgery combined
with adjuvant therapy, compared with radiation or systemic
therapy alone, can result in significantly better survival in
breast cancer patients with metastatic disease in the lung,
liver, brain, or sternum. As discussed above, several kinds
of bias might influence these results. Nonetheless, the data
are suggestive and support the need for well-designed clinical trials to determine the exact role of surgical intervention in patients with metastatic breast cancer. Such trials
will admittedly be difficult to implement. Not only are the
absolute numbers of eligible patients likely to be small, but
accrual of patients into clinical trials is a continuing challenge. As of 1991, only 1%-3% of the available patient population was being recruited into cooperative group adjuvant
trials, with only 10%-30% of eligible patients finally
enrolled in studies [62]. For breast cancer, less than 2% of
patients are included in clinical trials [63]. In the case of
patients with stage IV breast cancer, a significant barrier to
patient accrual may be reluctance of the patient or physician
to consider aggressive therapy in what has historically been
considered to be end-stage disease.
Across the four sites (lung, liver, brain, bone), better
patient outcome after surgery was associated with good performance status, long DFI after treatment of the primary
tumor, complete resection of the tumor, and restriction of
metastasis to single tumors or to multiple tumors at a single
site. Complete resection constitutes proper surgery for any
tumor, and it is not surprising that it would also have a significant effect on outcomes for metastastic lesions. In
metastasis to the lung, for example, complete resection can
offer 5-year survival rates as high as 50% compared with
the 18% associated with incomplete resection [19]. The last
criterion (restriction to a single tumor or a single site)
argues for the early detection of the metastatic lesion(s),
before more advanced disease progression occurs. Early
detection of lung, liver, and bone metastases would require
the routine use of chest x-rays, abdominal ultrasounds, and
bone scans as part of the routine follow-up for breast cancer. In the case of brain metastases, even very small lesions
generally result in neurological symptoms that are clinically detectable, removing the need for advanced imaging
techniques in asymptomatic patients.
In the practice guidelines of the National Comprehensive
Cancer Network [64], the current recommendations for follow-up of breast cancer patients are: A) history and physical
exam every 4-6 months for 5 years, then every 12 months; B)
mammogram every 12 months (or 6 months, after radiotherapy if breast-conserving surgery was used); and C) pelvic
exam every 12 months in women on tamoxifen, if the uterus
is present. These guidelines were based in part on the results
Surgery and Metastatic Breast Cancer
of a large multicenter trial conducted in Italy comparing outcomes in patients with differing follow-up protocols [65, 66].
One group of patients received yearly mammograms and
physical examinations, and the second group received intensive surveillance that included bone scans, liver sonograms,
chest x-rays, and laboratory tests in addition to the mammogram and physical exam. The results of the trial indicated that
the tests used in the intensive surveillance regimen did not
improve survival or influence quality of life and, thus, should
not be included in routine follow-up. However, as suggested
by Cocconi [67], it may not be surprising that the outcomes
in the two groups were similar, since the recommended treatment protocol would have been largely palliative, regardless
of when the metastasis was discovered. The question then
becomes: would the inclusion of these tests in routine breast
cancer follow-up be more cost effective if a different treatment protocol with the potential for an improved outcome
was recommended for patients with solitary metastases?
For bone metastases in the spine or long bones, it seems
unlikely that earlier detection would significantly alter current treatment recommendations. Since bone resections
constitute radical surgery, with extended and painful recovery times, most metastases would continue to be treated primarily with hormonal therapy or chemotherapy, with
surgery reserved for fracture reduction or stabilization.
Brain metastases, as mentioned above, are typically symptomatic from a very early stage, and patients would derive
little benefit from the addition of costly screening tests.
Metastasis to the liver is generally a late event, usually
accompanied by systemic disease. Ultrasound imaging is
effective in detecting hepatic lesions, but the cost to include
this in routine screening to detect the rare isolated event
may be prohibitive.
It may, however, be cost effective to reconsider the routine use of chest x-rays for follow-up of breast cancer
patients. This diagnostic tool would be effective in detecting
early metastasis to the lung or sternum, which often occurs as
a solitary lesion. Based on current estimates of breast cancer
incidence [68], this would involve screening 192,000 patients
per year for the detection of approximately 3,000 metastases
to the lung or sternum. In both of these sites, the use of surgical excision in addition to standard medical treatment has
been shown to significantly improve median survival.
As the treatment recommendations for breast cancer continue to evolve, so too does the definition of what constitutes
a “cure.” We are perhaps approaching a time where breast
cancer can be “cured” in the sense that it can be rendered
harmless. By moving away from the treatment paradigm
aimed at removing or destroying every cancerous cell, we
can redefine a “cure” as a prolonged period of survival without significant symptoms. Under this new paradigm, cancer
Singletary, Walsh, Vauthey et al.
can be thought of as being reduced to a commensal organism,
the biological equivalent of an epiphyte, such as Spanish
moss, that depends on the oak tree to live but does nothing to
249
harm its host organism. Metastatic breast cancer to the lung
or sternum, if detected early and treated aggressively, holds
the possibility of such a cure.
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