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Keywords:

  • surgery;
  • metastatic breast cancer;
  • stage IV;
  • indication

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

Evolving concepts of cancer biology and emerging evidence of a potential survival benefit from local surgery have raised the question of an expanded role for surgery in select patients with metastatic breast cancer (MBC). To determine whether such developments have influenced clinical practice, the authors evaluated surgical practice patterns in the study institution over the last 15 years.

METHODS

Two institutional databases were screened to identify patients with MBC who underwent breast surgery (1990–2005). Retrospective review was conducted to assess trends over time and to evaluate the role of surgery in the more modern era (1995–2005).

RESULTS

The overall frequency of mastectomy remained stable over time (1.7%); however, between early (1990–1995) and late (2000–2005) periods the rate of ‘symptom control’ mastectomy decreased (41% to 25%), whereas the rate of ‘local control’ mastectomy increased (34% to 66%). Conversely, the overall frequency of wide-local excision (WLE) increased over time (1995–2001), from 1% to 9% (P < .001) with no differences noted between rates of symptom control or local control procedures. In the modern era (1995–2005), 256 of 12,529 patients (2%) with MBC underwent breast surgery (33% mastectomy, 52% WLE); most frequently to ‘optimize local control’ (50%) and primarily in the setting of limited/stable distant disease. Surgery was performed for palliation in only 19% of patients. At a median follow-up of 33.9 months (range, 0–198.7 months), 136 of 256 patients (53%) in this cohort remained alive; 88% were free of local disease.

CONCLUSIONS

Although surgery in MBC has historically been reserved for palliation, the authors observed a decreasing rate of traditional ‘toilet mastectomy’ and a broadened surgical approach to the asymptomatic patient. When viewed in parallel with evolving concepts in cancer biology, these data reflect a change in the traditional approach to patients with MBC and warrant further investigation. Cancer 2008. ©2008 American Cancer Society.

Each year in the U.S., approximately 210,000 women are diagnosed with invasive breast cancer, of whom 6% will present with stage IV disease. In addition, despite advances in systemic treatments, approximately 30% of patients with potentially curable breast cancer will eventually develop metastases.1 Currently, metastatic disease is incurable and remains so because of a limited understanding of the molecular mechanisms of metastasis. The conventional model of metastasis teaches that the primary tumor is biologically heterogeneous and that metastatic potential is determined by rare subpopulations of cells that over time may acquire genetic alterations, in a stepwise manner, thereby facilitating metastatic dissemination.2, 3 However, to our knowledge, no direct evidence of this model has been documented in human tumors, and clinical observations continually challenge its basis.1, 4–6 Thus, the fundamental question of how a primary tumor becomes metastatic remains unanswered.

Challenged by this uncertainty, several new concepts of metastatic dissemination have been proposed. Microarray studies indicate that metastatic potential is an inherent, genetically predetermined property of the primary tumor cell expressed very early in its evolution. As such, tumor cells are programmed to metastasize to specific genetically predetermined sites where, in the presence of a favorable microenvironment, a tumor mass will form that ultimately infiltrates and destroys its host.7–15 Recent mathematical models have expanded this theory, suggesting that not only does this ‘escapee’ cell have the capacity to seed distant sites, but it may also metastasize back to the primary tumor (‘self-seed’), thereby contributing both to the ongoing growth and destruction at the site of primary disease, as well as to an ever-growing source of disseminating tumor cells.16 Within the context of metastatic breast cancer (MBC), this new theory of ‘self-seeding’ would strongly support complete excision of the primary tumor. However, conventional wisdom teaches that treatment should be ‘metastasis-directed’ and local therapy of the primary tumor should be reserved for symptom control.17, 18

As new insights into cancer biology are achieved in the laboratory, there has been a shift in our approach to systemic treatment with an increased focus on targeted therapy. The microarray data have shown promise as a useful prognostic marker for recurrence, and randomized trials using these data to select adjuvant treatment are under way.7, 8 Furthermore, agents that target cells of the tumor microenvironment are either in clinical trials or have been approved by the U.S. Food and Drug Administration for the treatment of MBC; antiangiogenic therapy serves as a good example.19 It is unclear, however, if these insights have resulted in a change in the approach to local disease. Emerging evidence suggests that for patients with limited metastatic disease, combining surgery, radiotherapy, and systemic therapy may provide a survival benefit.20 These data are also complemented by 3 recent publications that suggest a potential survival benefit from complete excision of the primary tumor in select patients with MBC.21–23 Although these studies have spurred discussion among physicians, the bulk of the data are from large centralized databases, and it is difficult to determine whether there has been any actual change in surgical practice patterns.20–22, 24–28 We examined the surgical practice patterns in our institution for patients with MBC to determine whether our surgical approach to locoregional disease has evolved with concurrent scientific and clinical developments over the past decade.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

With the approval of our Institutional Review Board, we screened 2 institutional databases to identify patients who underwent breast surgery (mastectomy or simple wide-local excision [WLE]) in the setting of stage IV disease. Procedures included mastectomy and simple WLE of either a breast primary or a chest wall lesion. Depending on the time period of diagnosis, staging was based on the fifth or sixth editions of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. We included patients who 1) presented with de novo stage IV breast cancer and thus had intact primary disease at the time of diagnosis, and 2) patients who progressed to stage IV disease after treatment for earlier-stage breast cancer. Patients in the latter group included those with recurrent local disease and synchronous metastatic disease or recurrent locoregional disease only (defined by the presence of chest wall disease or supraclavicular lymph node disease if diagnosed before 2002). Although the goal of the current study was to review the role of surgery in the face of stage IV disease as perceived by the treating surgeon at the time of presentation, we acknowledge that patients presenting with stage IV disease de novo may have been viewed differently by the surgeon than those progressing to stage IV disease. Thus, to limit potential biases and/or false conclusions, we attempted to distinguish between them as much as possible during the analysis.

Trends Over Time

We reviewed the records of patients treated at our institution over a 15-year period to test for ‘trends over time.’ The institutional operative database was screened (January 1990 to December 2001) to identify a historical cohort of patients who underwent breast surgery in the setting of stage IV disease. Medical records for patients in the historical cohort were reviewed to identify specific procedures performed (mastectomy or simple WLE) and to determine the indication for surgery. To identify a more modern cohort of patients, clinical databases were screened using International Classification of Diseases-ninth revision (ICD-9) codes for metastatic disease sites (January 1995 to December 2005). Exhaustive chart review was performed to select only those patients from the modern cohort who underwent ≥1 breast surgical procedures in the setting of MBC and to determine the indication for surgery. Although there was some time-overlap between both databases, together they provided data from which we could assess trends in surgical practice patterns over a 15-year time period.

Role of Local Surgery in the Modern Era

For a more in-depth examination of the role of surgery in the modern era, a retrospective review of the medical records of patients identified from the clinical database (1995–2005) was undertaken. Standard clinical and pathologic parameters at the time of MBC diagnosis were reviewed, including age, race, medical/breast cancer history, clinical findings, and nonsurgical and surgical management. The ‘extent of disease workup’ was undertaken at the discretion of the treating physician and, based on this, the patterns of disease were categorized by number of metastatic sites (1, 2, or ≥3). Those with solitary metastatic disease were subcategorized by location of disease (bone, visceral, or soft tissue).

Furthermore, in the modern cohort, surgical management was examined under the following headings: presence/absence of symptoms, time interval between MBC diagnosis and procedure, indication for surgery, procedure(s) performed, median hospital stay, complications, and outcome. Indications for surgery were extrapolated from chart review and categorized as: 1) symptom control; 2) confirmation of diagnosis, stage, or to establish estrogen receptor (ER)/progesterone receptor (PR)/HER-2/neu status to guide systemic therapy; 3) optimize local control in the setting of i) only site of disease, thus rendering the patient ‘stage IV, NED’; ii) only site of active disease, distant disease stable; iii) good response of local (or distant) disease to systemic treatment; and iv) plateau response of local disease to systemic therapy; and 4) unclear indications. Surgical treatment was described as per the procedure performed: modified radical mastectomy, total mastectomy, simple WLE, complex chest wall excision (ie, chest wall excision with reconstruction), axillary procedure, or ‘other local procedure.’ Outcomes were assessed in terms of the indication, and the endpoint of this study was clinical status at last known follow-up. All analyses were performed using SPSS software (version 11; SPSS Inc, Chicago, Ill).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Trends Over Time

Mastectomy

A total of 5623 patients had a mastectomy at our institution between January 1990 and December 2001, of which 1.7% (98 mastectomies) were undertaken for patients with stage IV disease.

The frequency of such procedures remained stable over time at (1.7%) when compared from 1990 through 1995 (41 of 2360 cases) and 1996 through 2001 (57 of 3263 cases), respectively. A further 28 patients with MBC underwent mastectomy between 2002 and 2005. Among all 126 mastectomies performed in the setting of stage IV disease between 1990 and 2005, 31% (39 mastectomies) were documented as traditional ‘toilet mastectomy’ to palliate symptoms, whereas 49% (62 mastectomies) were performed to ‘optimize local control’ in the absence of symptoms. Mastectomies were performed somewhat more frequently among patients presenting with MBC at the time of initial diagnosis (70 of 126 mastectomies; 55%) as compared with those patients who progressed to stage IV disease after previous treatment (56 of 126 mastectomies; 44%). Furthermore, patients presenting with MBC were more likely to undergo mastectomy for ‘symptom control’ compared with those who progressed to stage IV disease (34 of 70 patients vs 5 of 56 patients, respectively; P < .001). Mastectomy was performed for ‘local control’ with equal frequency among patients presenting with and progressing to MBC (35 of 70 patients vs 27 of 56 patients, respectively; P = not significant [NS]).

To assess for trends in surgical practice patterns over time, we compared 1) the pattern of presentation, and 2) the rates of ‘symptom’ versus ‘local’ control mastectomies performed between 2 time periods (1990–1995 and 2000–2005). Over time, mastectomies were performed with equal frequency among patients presenting with and progressing to stage IV disease. However, the rates of symptom control mastectomy decreased from 41% to 25%, and the rates of local control mastectomy increased from 34% to 66% (Fig. 1A).

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Figure 1. Trends in surgical practice patterns over time. (A) Mastectomy in patients (pts) with stage IV breast cancer. (B) Wide local excision in patients with stage IV breast cancer. MBC indicates metastatic breast cancer.

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Simple WLE

Similarly, between January 1990 and December 2001, a total of 2512 simple WLEs were performed at our institution, of which 106 (4%) were undertaken in the setting of stage IV disease. The frequency of such procedures increased from 1% (23 of 1630 simple WLEs) to 9% (83 of 882 simple WLEs) when compared among the 2 time periods (1990–1995 and 1996–2001, respectively; P < .001). An additional 45 patients with MBC underwent simple WLE between 2002 and 2005. Among all 151 simple WLEs performed in the setting of MBC between 1990 and 2005, 15% (22 simple WLEs) were documented as being performed for symptom control, whereas 46% (69 simple WLEs) were performed to ‘optimize local control’ in the absence of symptoms. Patients undergoing simple WLE procedures were more likely to have progressed to MBC after previous treatment for curable disease (119 of 151 patients; 79%), whereas the remaining 32 patients presented with MBC at the time of initial diagnosis. Furthermore, patients who presented with MBC were more likely to undergo simple WLE for ‘symptom control’ as compared with those who progressed to stage IV disease (7 of 32 patients vs 15 of 119 patients, respectively), whereas simple WLE for ‘local control’ was performed more frequently among patients progressing to MBC (12 of 32 patients vs 55 of 119 patients, respectively). These trends did not reach statistical significance.

Trends over time were analyzed in a similar fashion as they were with patients undergoing mastectomy. Over time, simple WLE was performed less frequently in patients presenting with MBC and more frequently among patients progressing to MBC, and we observed little difference in the rates of either ‘symptom’ or ‘local’ control for these procedures (Fig. 1B).

Role of Local Surgery in the Modern Era, 1995–2005

Among 12,529 patients with documented MBC seen at our institution between 1995 and 2005, 256 (2%) underwent ≥1 breast surgical procedures in the setting of stage IV disease. Of these, 84 patients (33%) presented with MBC at the time of initial diagnosis, whereas 172 patients (67%) had previously been treated for curable disease but had progressed to stage IV disease (median time to progression, 23.8 months [range, 2.3–455.5 months]). The mean age at the time of MBC diagnosis was 53.9 years (range, 22.9–90 years); 37% of patients were aged ≤50 years, and 12% were aged ≥70 years. Seventy-six percent of patients were Caucasian, 11% were African-American, 9% were Hispanic, and 4% were Asian. Both the age and ethnic distribution accurately reflects the total population of MBC seen at our institution during this period.

Upon diagnosis of stage IV disease, 157 of 256 patients (61%) presented with concurrent distant metastases. The remaining 99 patients (39%) were deemed to have stage IV disease because of the presence of chest wall metastases or supraclavicular lymph node disease diagnosed before 2002. Of these 99 patients, 17 (17%) subsequently developed distant metastatic disease before their surgical procedure. Thus, at the time of local surgery a total of 174 patients (68%) had distant metastatic disease and 82 patients (32%) had locoregional stage IV disease only. Of those with distant metastatic disease, 128 (74%) had solitary metastases (53 bone, 44 visceral, and 31 soft tissue), 30 (17%) had 2 sites of disease, and 16 (9%) had ≥3 sites of metastatic disease. Finally, upon diagnosis (thus prior to surgery), 85 patients (33%) received chemotherapy, 50 (20%) received hormonal therapy, 6 (2%) received trastuzumab, 4 (2%) received both hormonal therapy and trastuzumab, and 14 (5%) received radiotherapy to the breast.

The indication for locoregional surgery in the setting of MBC was clearly documented in 244 of 256 cases (95%) (Table 1). Overall, the most common indication was to optimize local control (128 of 256 cases; 50%); 48% of which (60 of 128 cases) were in the setting of ‘only site of disease, thus rendering the patient stage IV, no evidence of disease (NED) by surgery.’ The median time from diagnosis to surgery for local control was 11.7 months (range, 0–75.2 months) (Table 2). The most common ‘local control’ procedures performed included simple WLE (61 of 128 cases; 48%) or mastectomy (53 of 128 cases; 41%) (Fig. 2). ‘Local control’ procedures were performed with equal frequency among patients presenting with and progressing to MBC (Table 1). The median length of hospital stay for surgery was 1 day (range, 0–23 days) and the complication rate was 6% (1 postoperative bleed, 4 wound infections, and 2 delayed wound healing cases).

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Figure 2. Procedures performed in terms of indications for surgery. Simple WLE indicates wide local excision/chest wall excision; Complex CWE, chest wall excision with reconstruction; Other, supraclavicular lymph node biopsy (4 patients), scalene lymph node dissection (1 patient), and major duct excision (1 patient).

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Table 1. Indications for Surgery
IndicationTotal (n = 256)Patients presenting with stage IV disease (n = 84)Patients who progressed to stage IV disease (n = 172)
  1. Dx indicates diagnosis; NP, new primary tumor; M0, no distant metastases; M1, distant metastases; NED, no evidence of disease.

Symptom control49 (19%)30/84 (36%)19/172 (11%)
Ulcerating/fungating lesion332310
Pain615
Patient unable to cope431
Infection422
Bleeding211
Diagnosis/stage/status67 (26%)12 (14%)55 (32%)
Presented with metastases, confirm Dx880
Confirm stage (NP vs stage IV) (all M0)22121
Assess receptor status to guide treatment (all M1)37334
Optimize local control in the setting of…128 (50%)40 (48%)88 (51%)
Only site of active disease, thus rendering the patient “stage IV, NED” by surgery.60753
Only site of active disease, distant disease stable (all M1)552233
Good response of local (or distant) disease to systemic treatment (all M1)981
Plateau response of local disease to systemic therapy (all M1)431
Indication unclear12 (5%)2 (2%)10 (6%)
Table 2. Time Interval Between Diagnosis of Stage IV Disease and Surgery in Terms of Indication for Procedure
Indication (n = 256)Median time (range), months
Diagnosis/stage/receptor status (n = 67)0.2 (0–59.4)
Symptom control (n = 49)4.9 (0–77.1)
Optimize local control in the setting of… (n = 128)11.7 (0–75.2)

Among 128 patients undergoing local control procedures, 65 (51%) achieved negative surgical margins, 48 (38%) demonstrated positive or close surgical margins, and in the remaining 15 patients (12%) the margin status was not documented. A total of 41 patients (32%) recurred locally (median time to recurrence, 17.4 months [range, 2.9–141.3 months]). Of these, 25 patients (61%) had a previous resection with negative surgical margins, compared with 13 patients (32%) whose previous surgical margin status was positive/close (3 of 41 had unknown surgical margin status). Neither surgical margin status nor indication for surgery predicted local recurrence (Table 3). Nearly half of those patients who experienced a local recurrence underwent further surgery (20 of 34 patients; 59%). At a median follow-up of 35 months (range, 0.3–198.7 months), 73 of 128 patients (57%) remained alive, 85% of whom (62 of 73) were free of local disease.

Table 3. Outcome of Procedures Performed for Local Control With Median Follow-up of 35 Months
IndicationNo.No. of local recurrences (interval in mo)No. of re-excisionsFollow-up
NELDAWLDDOD
  1. NELD indicates no evidence of local disease; AWLD, alive with local disease; DOD, dead of disease; NED, no evidence of disease; M1, distant metastases.

Only site of active disease, thus rendering the patient “stage IV, NED” by surgery6023 (4.2–141.3)14/2331524
Only site of active disease, distant disease stable (all M1)5515 (2.9–127.7)4/1523527
Good response of local (or distant) disease to systemic treatment (all M1)93 (5.2–46.5)2/3711
Plateau response of local disease to systemic therapy (all M1)4103
Totals12841 (32%)20 (49%)62 (48%)11 (9%)55 (43%)

Confirmation of diagnosis, stage, or receptor status was the indication for surgery in 67 of 256 cases (26%) (Table 1). The most common ‘diagnostic’ procedure performed was a simple WLE (44 of 67 patients; 66%) (Fig. 2). The median time from MBC diagnosis to surgery was 0.2 months (range, 0–59.4 months) (Table 2). Such ‘diagnostic’ procedures were more frequent among patients who had progressed to MBC compared with those who presented with MBC (Table 1). The median length of hospital stay for surgery was 1 day (range, 0–8 days). The complication rate was 1.5% (1 wound infection). At a median follow-up of 38.9 months (range, 2.7–117.3 months), 37 of 67 patients (55%) remained alive, 95% of whom (35 patients) were without local disease.

Palliation of symptoms was the indication for surgery in only 49 of 256 cases (19%) (Table 1). The most common symptom reported was an ulcerated or fungating lesion (33 of 49 patients; 61%). The median time from presentation to surgery was 4.9 months (range, 0–77.1 months) (Table 2). Palliative procedures performed included: mastectomy (25 of 49 patients; 51%), simple WLE (21 of 49 patients; 43%), and complex chest wall excision with reconstruction (3 of 49 patients; 6%) (Fig. 2). Palliative procedures were more common among patients presenting with MBC than among those who progressed to MBC (Table 1). The median length of hospital stay for surgery was 2 days (range, 0–33 days) and the complication rate was 29% (14 of 49 patients [2 postoperative bleeds, 2 cardiopulmonary complications, and 10 wound complications]). At short-term follow-up of 1 month, 1 patient developed a symptom recurrence, and at 6 months after surgery 2 additional patients had developed a symptom recurrence (3 of 49 patients; 6%). At a median follow-up of 29 months (range, 0.7–124 months), 16 of 49 patients (33%) remained alive, 94% of whom (15 of 16 patients) were free of symptoms (Table 4).

Table 4. Procedures Performed for Symptom Control With a Median Follow-up of 29 Months (Range, 0.7–124 Months)
IndicationNo.Symptom recurrence no. (interval, days)Local recurrence* no. (interval, months)Follow-up
NELDAWLD, S−*AWLD, S+DOD
  • NELD indicates no evidence of local disease; AWLD, alive with local disease, S−, asymptomatic; S+, symptomatic; DOD, dead of disease.

  • *

    Asymptomatic local recurrence.

Ulcerated/fungating332 (27–57)6 (2.9–105.5)81*123
Pain633
“Unable to cope”422
Infection41 (137)2 (2–4.9)4
Bleeding21 (28.3)11
Total493 (6%)9 (18.4%)14 (29%)1* (2%)1 (2%)33 (67%)

Overall, at a median follow-up of 33.9 months (range, 0.3–198.7 months), 136 of 256 patients (53%) with MBC in this cohort remained alive. Among the original 82 patients who at the time of surgery were classified as having stage IV disease based on advanced locoregional disease alone, 55 of 82 (67%) remained alive, 84% of whom (46 of 55 patients) were free of local disease (median follow-up from surgery, 40.8 months); 34 of 82 patients (41%) developed distant metastases (median time from surgery, 18.3 months). Among the original 174 patients with distant metastases at the time of surgery, 81 patients (47%) remained alive, 90% of whom (73 patients) were free of local disease (median follow-up from surgery, 30.9 months).

Additional metastatic-directed therapy after local surgery included chemotherapy (119 of 256 patients; 47%), hormonal therapy (120 of 256 patients; 47%), trastuzumab (25 of 256 patients; 10%), hormonal therapy and trastuzumab (18 of 256 patients; 7%), and radiotherapy (59 of 256 patients; 23%). Metastatic-directed surgery was also performed for 21 patients (Table 5).

Table 5. Procedures Performed for Metastatic Disease After Local Surgery
 No. (n = 21)Interval from local (breast) surgery to metastatic site procedure (range, months)
  1. VAT indicates video-assisted thoracoscopy; ICP, intracranial pressure; IVP, intraventricular peritoneal; LN, lymph node.

Orthopedic surgery
Pathologic fracture716.5 (0–47.5)
Cauda equina syndrome257.5 (26.1–88.9)
Thoracic surgery
VAT/wedge resection71.2 (0–38.7)
Bronchoscopy/laser ablation130.1
Neurosurgery
Craniotomy240.5 (33.1–48.1)
ICP/IVP shunt19.2
General surgery
Inguinal LN dissection112.4

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

For patients with MBC, conventional wisdom teaches that surgical excision of an asymptomatic primary tumor is unlikely to offer the patient any survival benefit.29 This approach is based on ideas put forth by Celsius (30 BC to AD 38) and Galen (AD 129–199) who established the first staging systems of cancer, and whose doctrine formed the basis of our treatment until the mid-1800s, when technical innovations facilitated pioneering scientists to lay the foundations of modern biology.30 Circa 1838, Schleiden and Schwann published “Cell Theory,”31, 32 and shortly after, Virchow33 expanded this to explain the effects of disease in human tissues. Virchow described breast cancer as a disease that begins as a single focus in the breast and expands locally by migrating along lymphatic channels toward the axillary lymph nodes, gradually conquering the axilla and spreading along tissue planes to the skeleton and vital organs. This landmark observation ignited a fascinating surgical evolution in terms of localized (operable) disease6, 7, 34–37; and some 50 years later, when investigators put forth the concepts of biologic predeterminism and systemic therapy,38–40 the focus of nearly all surgical clinical trials remained on early-stage, localized disease. Although these trials have shown that for patients with stage 0 through III breast cancer, variations in local treatment do affect survival,41 the lack of data regarding stage IV disease makes it difficult to interpret such findings within the context of MBC.

Thus, in the current era of improving survival with targeted systemic therapy,42 the role of local treatment in MBC remains untested. Nonetheless, the following clinical observations have been made: 1) although breast cancer remains a fatal disease, the median survival times for patients with stage IV disease are improving40; 2) the development of more sophisticated imaging technology has improved the detection of small foci of distant disease, suggesting that today's stage IV patient population is very different from that of 15 to 20 years ago24, 25; 3) if patients with limited metastatic disease can be rendered clinically free of disease by local treatment, there is the potential of achieving a complete remission from systemic therapy, and select patients may remain disease free for longer periods of time43–46; 4) in select patients, surgical resection of the primary tumor may improve metastatic progression-free survival and breast cancer mortality18, 20; and 5) for select patients with single or multiple metastatic lesions restricted to 1 organ (lung, liver, brain, or bone), metastatectomy combined with systemic and/or radiotherapy may prolong survival.21, 22 Although these findings are inherently limited by selection and publication biases, and in some cases by their retrospective nature, they raise intriguing questions. When viewed in parallel with the new biologic concepts of breast cancer metastasis, they challenge the traditional surgical approach to stage IV disease.

In our modern population of patients with MBC, the rate of local surgery among patients with stage IV disease was 2%. This low rate of surgery is in contrast to recently published population-based series that reported rates of local surgery of up to 57%.21, 23 Possible explanations for this difference include: 1) the inherent limitations in obtaining data regarding timing of surgery with respect to timing of “staging” in large population databases (ie, patients may have undergone a staging work-up revealing distant metastasis after the local breast procedure had already been performed), and 2) because the point of entry to our institution for the majority of patients with stage IV disease is through the medical oncology service, it is likely that only a minority of patients with stage IV disease are seen by the surgical service.

It is interesting to note that among patients with MBC undergoing local surgery at our institution over the last decade, the primary role of surgery was to optimize local control, most often in the absence of detectable distant disease or in the setting of limited/stable metastatic disease. At a median follow-up of 33.9 months, 53% of patients remained alive, and 87% demonstrated no evidence of local disease. This was a retrospective study focusing on surgical practice patterns; it was not designed to determine any survival advantage from surgery, although recent observations by others suggest that local treatment might have a greater influence on breast cancer survival than previously believed (Table 6).18–20 On the basis of a retrospective review of the National Cancer Database, Khan et al.21 reported that surgical resection in patients with MBC afforded patients a survival benefit. This observed benefit increased steadily, from those who underwent no surgery, to those who underwent surgery with positive margins, to those undergoing resection of the primary tumor with negative margins (3-year survival rates of 17.3%, 26%, and 35%, respectively; p < .0001). It is interesting to note that axillary lymph node dissection did not appear to affect survival.18 Adjusting for factors such as number and site of metastases, additional studies19, 20 add strength to the hypothesis that local tumor burden may be a predictor of outcome.24, 25, 45 Although subject to many inherent limitations, these studies suggest that in a manner akin to metastatic renal,47, 48 ovarian,49, 50 and colorectal cancer51 the primary tumor may be considered a site of metastasis and resected for potential benefit. Furthermore, in light of the recent evidence that variations in local treatment for early stage breast cancer affect survival,37 is it unreasonable to suggest that in a select population of patients with MBC, optimizing local control by removing the primary tumor may confer a survival benefit?

Table 6. Results of 3 Studies Evaluating the Role of Surgery in Patients With Stage IV Breast Cancer and Intact Primary Tumors
StudySourceDiagnostic criterianNo. of patients who underwent surgery (%)Study endpointFindings
  1. NCDB indicates National Cancer Data Base; AJCC, American Joint Committee on Cancer; OS, overall survival; HR, hazards ratio; 95% CI, 95% confidence interval; NA, not applicable; UICC, International Union Against Cancer; PFS, progression-free survival; RR, relative risk.

Khan, 200221Population-based study (NCDB), 1990–1993AJCC16,0239162 (57.2%)OSHR (95% CI)
No surgery: NA
Surgery, negative margins (n = 3099) 0.61 (0.58–0.064), P ≤ .0137
Surgery, positive margins (n = 2326)
0.75 (0.71–0.79), P < .1035
 
Rapiti, 200623Population-based study (Geneva Cancer Registry), 1977–1996UICC300127 (42.3%)5-y breast cancer-specific survivalAdjusted HR (95% CI)
No surgery: NA
Surgery, negative margins (n = 61)
0.6 (0.4–1.0), P = .05
Surgery, positive margins (n = 33) 1.3 (0.8–2.1)
Surgery, unknown margins (n = 33) 1.1 (0.7–1.7)
Babiera, 200622Single institution study (University of Texas M.D. Anderson Cancer Center), 1997–2002AJCC24482 (33.6%)PFS and OS (median follow-up 32.2 mo)RR (95% CI)
No surgery: NA
Surgery, PFS: 0.54 (0.38–0.77)
P < .0007
Surgery, OS: 0.5 (0.21–1.19)
P < .12

The traditional goal of surgery in MBC is to palliate symptoms for quality of life. Yet in our modern cohort, symptom palliation was the indication for surgery in <20% of cases. In our historical cohort there was a similar trend toward fewer truly palliative mastectomies (41% in 1990–1995 to 25% in 2000–2005; P < NS) and more simple WLE (1% in 1990–1995 vs 9% in 1996–2001; P ≤ .001) being performed over the last decade. Possible explanations for this apparent change in surgical approach in the setting of symptom palliation include better local responses to systemic therapy (supported by the finding that half of the patients included in this report underwent surgery nearly 1 year after the diagnosis of stage IV disease), as well as a changing stage IV population, whereby the increased use of preoperative imaging leads to the diagnosis of metastatic disease in the setting of smaller (T1-T2) primary tumors, which are less likely to be symptomatic.18, 20, 24, 25

It is interesting to note that among those patients undergoing true palliative surgery for ulcerated/bleeding/infected tumors, 72% (28 of 39 patients) of patients have died of disease, which is in contrast to the 43% (55 of 128 patients) of patients undergoing nonpalliative surgery who had died of disease at the time of last follow-up (P < .0018). This finding supports the hypothesis that stage IV disease represents a group of biologic subtypes with varied natural history and challenges us to identify those patients who may truly benefit from removal of the primary tumor outside the setting of palliation. Furthermore, the minority of patients requiring palliative surgery for symptoms highlights the need for surgeons to consider the concept put forth by the American College of Surgeons that palliation should include the management of an incurable disease at any point in time from diagnosis onwards, not just in the face of intractable symptoms.52 As such, the role of surgery may include optimizing quality of life by minimizing physical, psychologic, social, and psychosexual sequelae of the disease.52, 53

In conclusion, new concepts of cancer biology continue to improve our understanding of metastasis. It is clear that the fatality of cancer results from the widespread dissemination of primary tumor cells to distant sites, and that efforts to reduce tumor load and prevent further dissemination are likely to be necessary to convert this fatal disease into a chronic illness. Although such insight has led to the development of novel systemic therapies, perhaps it should also be considered when viewing the indications for surgery. Whether surgical therapy directed at locoregional disease improves survival awaits validation; yet, as clinical scientists, we are challenged and encouraged to bring these new concepts of tumor biology to the bedside.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We thank Jane E. Howard, Data Coordinator Breast Disease Management Team, and Jennifer Delli Carpini, Julia Brockway, Katherine Lavigne, Sheena Singh, and Michelle Stempel, Research Study Assistants, Department of Surgery, Memorial Sloan-Kettering Cancer Center

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  • 1
    Jemal A,Siegel R,Ward E, et al. Cancer statistics. CA Cancer J Clin. 2006; 56: 106130.
  • 2
    Poste G,Fidler IJ. The pathogenesis of cancer metastasis. Nature. 1980; 283: 139146.
  • 3
    Fidler IJ,Kripke ML. Metastasis results from pre-existing variant cells within a malignant tumor. Science. 1977; 197: 893895.
  • 4
    Ramaswamy S. Cancer transcriptomics: modeling metastasis. Eur J Hum Genet. 1996; 14: 12.
  • 5
    Brinkley D,Haybittle JL. A 15 year follow up study of patients treated for carcinoma of the breast. Br J Radiol. 1968; 41: 215221.
  • 6
    Brinkley D,Haybittle JL. The curability of breast cancer. Lancet. 1975; 2: 914.
  • 7
    Van de Vijver MJ,He YD,Van't Veer LJ, et al. A gene expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002; 347: 19992009.
  • 8
    Van't Veer LJ,Dai H,Van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002; 415: 530536.
  • 9
    Ramaswamy S,Ross KN,Lander ES, et al. A molecular signature of metastasis in primary solid tumors. Nat Genet. 2003; 33: 4954.
  • 10
    Weigelt B,Glas AM,Wessels AF, et al. Gene expression profiles of primary breast tumors maintained in distant metastases. Proc Natl Acad Sci U S A. 2003; 100: 1590115905.
  • 11
    Minn AJ,Gupta GP,Siegel PM, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005; 436: 518524.
  • 12
    Minn AJ,Kang Y,Seranova I, et al. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest. 2005; 115: 4455.
  • 13
    Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889; 1: 571573.
  • 14
    Kang Y,Siegel PM,Shu W, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003; 3: 53749.
  • 15
    Bissell MJ,Labarge MA. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell. 2005; 7: 1723.
  • 16
    Norton L,Massague J. Is cancer a disease of self-seeding? Nat Med. 2006; 12: 875878.
  • 17
    National Comprehensive Cancer Network. Clinical practice guidelines in oncology: breast cancer. Version 3. Fort Washington, PA: National Comprehensive Cancer Network; 2003.
  • 18
    Chung CT,Carlson RW. Goals and objectives in the management of metastatic breast cancer. Oncologist. 2003; 8: 514520.
  • 19
    Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Cell. 2005; 7: 513520.
  • 20
    Singletary SE,Walsh G,Vauthey JN, et al. A role for curative surgery in the treatment of selected patients with metastatic breast cancer. Oncologist. 2003; 8: 241251.
  • 21
    Khan SA,Stewart AK,Morrow M. Does aggressive local therapy improve survival in metastatic breast cancer? Surgery. 2002; 132: 620627.
  • 22
    Babiera G. Effect of primary tumor extirpation in breast cancer patients who present with stage IV disease and an intact primary tumor. Ann Surg Oncol. 2006; 13: 776782.
  • 23
    Rapiti E. Complete excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis. J Clin Oncol. 2006; 24: 27439.
  • 24
    Vlastos G,Smith DL,Singletary SE, et al. Long-term survival after an aggressive surgical approach in patients with breast cancer metastasis. Ann Surg Oncol. 2004; 11: 869874.
  • 25
    Pocard M,Pouillart P,Asselain B,Falcou MC,Salmon RJ. Hepatic resection for metastatic breast cancer metastases: results and prognosis (65 cases). Ann Chir. 2001; 126: 413420.
  • 26
    Carmichael AR,Anderson ED,Chetty U,Dixon JM. Does local surgery have a role in the management of stage IV breast cancer? Eur J Surg Oncol. 2003; 29: 1719.
  • 27
    Morrow M,Goldstein L. Surgery of the primary tumor in metastatic breast cancer: closing the barn door after the horse has bolted? J Clin Oncol. 2006; 24: 26942696.
  • 28
    Morrow M. Improved survival in metastatic breast cancer following total excision of the primary tumor. Nat Clin Pract Oncol. 2007; 4: 1415.
  • 29
    Delarue NC,Peters V,Anderson WS,Starr J. A re-evaluation of the place of major extirpation in the management of patients with metastatic mammary carcinoma. CMAJ. 1967; 96: 637651.
  • 30
    Baum M,Demeicheli R,Hrushesky W,Retsky M. Does surgery unfavourably perturb the “natural history” of early breast cancer by accelerating the appearance of distant metastases? Eur J Cancer. 2005; 41: 508515.
  • 31
    Schleiden MJ. Arch Anat Physiol. Wiss Med. 1838; 13: 137176.
  • 32
    Schwann T. Mikroskopische Untersuchungen uber die Ubereinstimmung in der Struktur und dem Wachstum der Tiere und Pflanzen. Berlin: Sander'schen Buchhandlung; 1839.
  • 33
    Virchow R. Die Krankhaften Geschwulste. Vol 1. Berlin: Hirshwald Publishers; 18631873.
  • 34
    Halsted WS. The training of the surgeon. In: HalstedWS, ed. Surgical Papers. Vol 2. Baltimore: Johns Hopkins Press; 1924.
  • 35
    Lewis D,Rienhoff WF. Results of operations at the Johns Hopkins Hospitals for cancer of the breast: performed at the Johns Hopkins Hospitals from 1889 to 1931. Ann Surg. 1932; 95:336400.
  • 36
    Meier P,Ferguson DJ,Karrison T. A controlled trial of extended radical mastectomy. Cancer. 1985; 55:880891.
  • 37
    Lacour J,Le M,Caceres E, et al. Radical mastectomy versus radical mastectomy plus internal mammary dissection. Ten year results of an international cooperative trial in breast cancer. Cancer. 1983; 51: 19411943.
  • 38
    Dodds EC. Chemotherapy in the treatment of malignant disease. BMJ. 1949; 2: 11911193.
  • 39
    MacDonald I. Biological predeterminism in human cancer. Surg Gynaecol Obstst. 1951; 93: 129152.
  • 40
    Fisher B. A biological basis for the surgical treatment of clinically curable breast cancer. Bull Soc Int Chir. 1972; 31: 604609.
  • 41
    Clark M,Collins R,Darby S, et al., and the EBCTCG. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005; 366: 20872106.
  • 42
    Giordano SH,Buzdar AU,Kau SW, et al. Improvement in breast cancer survival: results from M.D. Anderson Cancer Center protocols from 1975–2000. Proc Am Soc Clin Oncol. 2002; 21: 54a.
  • 43
    Holmes FA,Buzdar AU,Kau SW, et al. Combined-modality approach for patients with isolated recurrences of breast cancer (IV-NED): the M.D. Anderson experience. Breast Dis. 1993; 7: 720.
  • 44
    Rivera E,Holmes FA,Buzdar AU, et al. Fluorouracil, doxorubicin, and cyclophosphamide followed by tamoxifen as adjuvant treatment for patients with stage IV breast cancer with no evidence of disease. Breast J. 2002; 8: 29.
  • 45
    Borner M,Bacchi M,Goldhirsch A, et al. First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. Swiss Group for Clinical Cancer Res. J Clin Oncol. 1994; 12: 20712077.
  • 46
    Nieto Y,Nawaz S,Jones RB, et al. Prognostic model for relapse after high-dose chemotherapy with autologous stem-cell transplantation for stage IV oligometastatic breast cancer. J Clin Oncol. 2002; 20: 707718.
  • 47
    Halbert RJ,Figlin RA,Atkins MB, et al. Treatment of patients with metastatic renal cell cancer: a RAND Appropriateness Panel. Cancer. 2006; 107: 23752383.
  • 48
    Campbell SC,Flanigan RC,Clark JI, et al. Nephrectomy in metastatic renal cell carcinoma. Curr Treat Options Oncol. 2003; 4: 363372.
  • 49
    Du Bois A,Harter P. The role of surgery in advanced and recurrent ovarian cancer. Ann Oncol. 2003; 17( suppl 10): x235x240.
  • 50
    Angioli R,Palaia I,Damiani P, et al. Up-date on cytoreductive surgery in the management of advanced ovarian cancer. Minerva Ginecol. 2006; 58: 459470.
  • 51
    Ruo L,Gougoutas C,Patay PB, et al. Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for asymptomatic patients. J Am Coll Surg. 2003; 196: 722728.
  • 52
    Surgical Palliative Care Task Force of the Division of Education, American College of Surgeons. The Surgeon and Palliative Care 2001. Available at: www.facs.org/palliativecare Accessed September 17, 2007.
  • 53
    Krouse RS,Jonasson O,Milch RA, et al. An evolving strategy for surgical care. J Am Coll Surg. 2004; 198: 149155.