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Surgical Oncology (2007) 16, 249–257

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REVIEW

Surgery for palliation and treatment of advancedbreast cancer

Michael Alvaradoa, Cheryl A. Ewinga,�, Dino Elyassniab, Robert D. Fosterb,E. Shelley Hwanga

aDivision of Surgical Oncology, Department of Surgery, University of California, San Francisco, USAbDivision of Plastic Surgery, Department of Surgery, University of California, San Francisco, USA

Contents

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Surgery for palliation of advanced breast cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250Surgical options. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

Definitive local surgery in metastatic breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252Surgery for distant disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

Background

Until the last half century, the history of palliative surgeryfor breast cancer has been one of extensive, and oftenheroic measures undertaken in an effort to provide somecomfort and quality of life to individuals with locallyadvanced disease. History provides numerous accountsdating back more than 3000 years of how local wound issueshave been the predominant source of fear and morbidity forthose afflicted with breast cancer [1]. However, aggressivepalliative procedures were at best dangerous, and at worstthemselves the basis of such terrifying distress, that manywomen came to dread treatment more than the diseaseitself.

The extirpative goal of palliative surgery has not under-gone significant change, with the objective remaining thecomplete resection of all appreciable gross disease. How-

nt matter & 2007 Published by Elsevier Ltd..2007.08.007

thor.

heryl.ewing@ucsfmedctr.org (C.A. Ewing).

ever, the range of surgical options available for breastreconstruction, chest wall soft tissue coverage and metas-tasectomy are more numerous and reliable than everbefore, resulting in greater individualization of a palliativeapproach and the expectation of better long-term out-comes. Creative uses of pedicled composite flaps haveexpanded the ability to provide reliable coverage forextensive tissue defects. Microsurgical techniques haveallowed greater freedom in selection of both donor andrecipient sites, and are much more robust than in previousyears. Techniques to manage metastatic sites have incorpo-rated adjunctive radiotherapy and cryotherapy. Advances inpreoperative patient education, as well as perioperativecare and monitoring have also played an important role inimproving mortality and morbidity from what can frequentlybe complex, extensive procedures.

A current discussion of the role of surgery in advancedbreast cancer would be incomplete without consideration ofthe management of the intact primary in patients withmetastatic disease. One of the critical issues currentlyimpacting surgical consideration in the setting of advanced

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M. Alvarado et al.250

breast cancer is the remarkable improvement in themanagement of patients with metastatic disease.As systemic treatment such as chemotherapy and hormonaltherapy have become ever more effective, the mediansurvival of women with metastatic disease has continued toimprove, as has the management of symptoms resultingfrom distant disease sites. Thus, new clinical questions haveemerged regarding surgery of the primary site in thosewomen with metastatic disease and a resectable intactprimary tumor.

More effective systemic therapy as well as the addition oftargeted biologics to systemic treatment has the potentialto render ‘‘cure’’ in those with known metastatic disease. Intwo small studies, trastuzumab-containing chemotherapyregimens resulted in a 10% complete response rate in womenwith metastatic disease [2,3]. Such studies support a likelyincrease in patients with stage IV surgery who may in fact becandidates for curative, as opposed to palliative resection.The use of palliative surgery may thus become part of theparadigm of targeted therapy, where its use in treatment ofwomen with stage IV disease may be reserved for thosewomen most likely to experience durable cure fromaggressive surgical treatment.

Very little data are available on which to base treatmentrecommendations for such groups of patients. The effect ofexcision of the primary tumor in metastatic sites isunknown, and few studies show concordant findings.However, even if effective, the intent of such surgery (i.e.palliative or curative) is unclear. Moreover, the extent oflocal surgical treatment also remains highly controversial.

These controversies are not likely to diminish. Despitewidespread awareness of the importance of breast cancerscreening and early detection, many patients are still foundto harbor metastatic disease at diagnosis. From 1985 to2003, the proportion of newly diagnosed women with distantdisease at presentation remained at 6% (Figure 1a). Thesepatients continue to have a grave prognosis, with a mediansurvival of less than 2 years (Figure 1b). However, as womensurvive longer with metastatic disease, clinicians will beincreasingly faced with the question of when to intervenesurgically in these patients.

The following provides an overview of the evolving role ofpalliative surgery in the management of both locally advancedand metastatic breast cancer. Specifically, we discuss theutility of palliative surgery in improving local tumor controlwith adequate tissue coverage. However, we will also reviewwhether surgery for stage IV patients may impact and extendoverall survival from advanced breast cancer.

Surgery for palliation of advanced breastcancer

Indications

Despite major advances in breast cancer treatment, surgerycontinues to play a major role in the local control ofadvanced breast cancer as an effective palliation for thepain, bleeding, infection and malodorous drainage that canaccompany locally advanced breast cancer. Due to oftenextensive spread, radical surgical extirpation is oftenrequired, usually in the form of a modified radical or radical

mastectomy. Effort is expended to spare the majorneurovascular structures even in the setting of gross axillarydisease, as their excision can result in significant morbiditywithout clearly demonstrated benefit in this high-riskpopulation with limited life expectancy. The goal of suchpalliative surgery is to resect all gross disease to negativemargins, as this will accord the patient the best opportunityfor durable local control. The resultant large defects willoften not close primarily, thus requiring some form ofreconstructive closure.

In addition to large defects from primary resection,reconstructive surgery may be needed for the treatment ofrecurrent breast cancer, post-radiation ulcers and unstableskin that will not tolerate adjuvant radiation. Often, theseprocedures are performed following a course of preopera-tive anthracycline and taxane-based chemotherapy, and thenature of the clinical situation may also often requirethe use of postoperative adjuvant radiation. Based on theextent of spread, these defects can be quite complex andmay include substantial loss of skin with partial- to full-thickness chest wall defects. The goal in these patients is toprovide expeditious wound closure with minimal morbidityso as not to delay adjuvant treatment, while at the sametime using good quality tissue that can withstand radiation.

Due to the relatively poor prognosis in this patientpopulation, breast mound reconstruction using autologoustissue or breast implants is traditionally not encouraged andcan potentially delay adjuvant treatment. However, somehave recently proposed that an aesthetic reconstruction beoffered to patients with advanced disease in light ofimproving survival with multimodality treatment. Chinet al. published a series of 23 patients with inflammatorybreast cancer (stage IIIB or IV) who underwent breast moundreconstruction [4] (Figure 2). The authors found significantpsychological benefits without a negative effect on survival,and therefore supported offering breast reconstruction in thisgroup. Multiple other studies have shown that patients withstage III cancer who have undergone reconstruction havesimilar outcomes as compared to patients who have not hadreconstruction [5–7]. This remains a controversial topic, but assystemic treatments improve, breast reconstruction will likelybe available to patients with more advanced disease.

Surgical options

Many reconstructive methods exist, the choice of whichdepends upon the characteristics of the wound, extent ofresection and patient comorbidities. For the most extensivewounds that involve a full thickness portion of the chestwall, gortex or marlex mesh is typically used with or withoutthe use of methylmethacrylate to reconstruct the chestwall. This then requires the use of a flap to providevascularized tissue to cover the prosthetic material. Onthe other hand, if the chest wall is intact including muscle atthe base of the wound (i.e. pectoralis major, serratusanterior, external oblique and rectus abdominis) then skingrafting alone may be an option and provides a simple, rapidmethod of wound closure. However, this is associated withpoor cosmesis and can be associated with increasedrecipient site morbidity and graft loss with radiation [8].To provide a more vascular wound bed for a skin graft there

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Figure 1 (a) Proportion of newly diagnosed breast cancers with distant disease at diagnosis, by race and year of diagnosis [55].(b) Overall survival following breast cancer diagnosis: effect of disease extent at presentation [55].

Surgery for palliation and treatment of advanced breast cancer 251

are several reports using a pedicled omental flap with a skingraft that have achieved good results [9–11]. In addition tothe requirement for a skin graft, the major drawback to thismethod is the need for a laparotomy and its attendantpotential morbidity. However, the use of laparoscopic flapharvest has decreased the morbidity of this procedure.

Currently, the most commonly used methods for coverageinclude local musculocutaneous and fasciocutaneous flaps.The latissimus dorsi (LD) and rectus abdominis (TRAM orVRAM, which represents the transverse or vertical design ofthe skin paddle) are the most commonly used local muscleflaps. The LD flap was the first muscle flap used to cover aradical mastectomy site in 1896 by Tansini. This muscle isbased on the thoracodorsal vessels and rotated from thesuperficial posterior trunk. A skin paddle up to 7 cm in widthcan be used with this flap and still permit direct donor siteclosure. This is a reliable flap that can cover the ipsilateral

hemithorax and sternum. Apffelstaedt reported a series of83 LD flaps used to cover defects from locally advancedbreast cancer [12]. Skin grafting was required for the donorsites in all cases due to the large size of the flaps. In 7 of 83cases there was minor flap loss that healed without anyspecific therapy. Flap complications resulting in delay ofpostoperative radiation occurred in only one case. Eighty of83 patients obtained permanent wound closure. Only onepatient did not achieve a healed wound prior to death andtwo patients had local recurrence that resulted in anulcerating wound.

As with the LD flap, the TRAM flap is also very reliable. Itis a pedicled flap based on the superior epigastric vesselsand can usually mobilize more skin than the LD flap and stillallow direct donor site closure. A fleur de lys pattern for therectus abdomis flap has been described to address theneed for large defects that may also require chest wall

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Figure 2 (a) Fifty young female with bilateral stage IIIB breastcancer. (b) Defect after excision of the right mass. Thepectoralis was intact and went on to be skin grafted success-fully. The left side was closed primarily.

M. Alvarado et al.252

reconstruction [13]. However, the TRAM flap has a higherrate of delayed complications associated with abdominalwall laxity or hernia. Mohamed et al. describe using this flapwith excellent results to cover large defects in a series of 38patients with locally advanced breast cancer [14]. Therewere six cases of partial flap loss that healed and fourpatients who complained of an epigastric bulge, but therewere no reported abdominal hernias. There are lesscommonly used muscle flaps described in the literatureincluding the pectoralis major flap and external obliqueflap. The external oblique flap is composed of skin from theepigastrium to the umbilicus, and from the axillary line tojust beyond the midline. It is raised to include the externaloblique muscle. Bogossian et al. described the use of theexternal oblique myocutaneous flap in 20 consecutivepatients to cover large defects and reported minimalcomplications [15]. The authors found this flap to be anexcellent choice for large ipsilateral to central chest walldefects for many reasons including technical ease andminimal donor site morbidity.

Aside from muscle flaps, the thoraco-abdominal flap (TA)is the primary option for coverage of these large defects.This is a fasciocutaneous rotation advancement flap thatutilizes the skin and soft tissue of the anterior abdominal

wall. They are based medially or laterally depending uponthe location of the wound. Lateral flaps are based onperforating branches of the lumbar and subcostal vessels atthe anterior border of the LD, and medial flaps are based onperforators from the deep epigastric vessels at the border ofthe rectus abdominis. These flaps are similar in design to theexternal oblique myocutaneous flaps but exclude the deepermuscle layer. In a study done by Deo et al. comparing theseflaps to LD and TRAM flaps, both groups had similar overallmorbidity and tolerance to postoperative radiation [16].However, the TA flaps were associated with a significantlyshorter operative time, less blood loss and shorter hospitalstay. Based on its simplicity and comparable results to otherflaps the authors recommend the TA flaps as the best firstoption.

Although pedicled flaps are generally the first choice forchest wall reconstruction, free flaps with microvascularanastamoses are considered for defects extending beyondthe reach of the pedicled flap, as a second option followinginitial reconstruction with a pedicled flap, or when thepedicled flap or its vascular supply have been included in thefield of resection. Although not commonly used, they haveexcellent versatility and are sometimes the only reconstruc-tive option available to provide cover extensive compositetissue defects. The most common free flaps used in thissetting are based on the tensor fascia latae, rectus femorisand TRAM. Several series have reported very low mortalityand flap loss rates with free flaps [17,18], making this areliable option in patients with considerable tissue loss fromresection of locally advanced disease. Most recently the useof DIEP flaps have been reported in this patient populationwith low morbidity and little impact on adjuvant treatmentplanning [19].

In summary, although local symptoms from advancedbreast cancer can be devastating, there are numerousreconstructive options using both pedicled and free tissueflaps that can facilitate a definitive palliative oncologicexcision, regardless of the extent of extirpation required.Treatment planning between the surgical oncology andreconstructive teams is essential to a good outcome, andwill allow selection of the most appropriate surgicalapproach.

Definitive local surgery in metastatic breastcancer

Historically, surgical resection of primary tumors in patientswith stage IV disease had been reserved for palliativepurposes. However, recent studies have also demonstrated apossible survival advantage for stage IV patients whoundergo local surgery for intact primary tumors. Althoughit was previously thought that resection of the primarytumor could accelerate metastatic growth by eliminatinginhibitors of angiogenesis [20], there does seem to be aselect group of stage IV patients who appear to benefit fromlocal regional control.

Treating the primary tumor in patients with metastaticdisease is not a novel idea within the oncology discipline.Systemic therapies accompanied by primary surgical controldirected at other organ sites have shown promising results aswell [21–26]. Recent studies of stage IV colorectal, gastric

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Surgery for palliation and treatment of advanced breast cancer 253

and renal cell carcinoma have all shown a possible survivaladvantage when undergoing resection of the primary in thesetting of distant metastases. As systemic therapies forbreast cancer continue to improve, it is increasinglyrelevant to question whether reduction in local tumorburden could lead to a survival benefit.

New models of cancer progression lend support to theconcept of locoregional control in the setting of stage IVbreast cancer. One such theory invokes the observation thatcancer patients are typically immunosuppressed and thuslack the ability to respond to their tumors [27–29]. A recentstudy used a mouse model to monitor immune responses inmice with metastatic disease [30]. Mice with intact primarytumors were compared to animals whose primary tumor hadbeen surgically excised. The study found that immunosup-pression was reversed following surgical resection of theprimary tumor. The authors describe the production ofcirculating cytokines by the primary tumor that inhibit T-cellactivation. This leads to a decrease in immune surveillanceand allows for tumor progression. Restoration of immunecompetence by surgical resection of the primary tumorcould therefore render the metastases more vulnerable tosystemic therapy.

With the identification of circulating tumor cells (CTC) inthe blood and disseminated tumor cells (DTC) in the bonemarrow of breast cancer patients, the concept of metastasisas a late event in tumor progression is being challenged.Greater than 20% of patients with stage I disease are at riskof developing distant metastases and the identification ofmicrometastases in the blood and bone marrow are likelymarkers of poor disease-free and overall survival [31–35].Interestingly, genomic analysis of metastases (including CTCand DTC) and the primary tumor have been shown to differ[36–38]. Because these two cell populations do not share thesame genetic signature, they would likely not respond to thesame systemic therapy. This argues for surgical resection ofthe primary tumor and focused systemic therapy for themetastatic disease directed, potentially, by its geneticsignature.

Although rigorous, prospectively gathered data support-ing surgical therapy for stage IV breast cancer patients arelacking, some retrospective studies lend support for resec-tion of the primary tumor in patients with distant disease. In2002, a review of stage IV breast cancer patients from theNational Cancer Data Base (NCDB) of the American Collegeof Surgeons (ACS) evaluated over 16,000 patients [39].Criteria for selection included: (1) primary site as breast, (2)reported as clinical or pathologic AJCC stage IV, (3) clinicalor pathologic evidence of metastasis and (4) positiveevidence of primary tumor. Patients were classified intotwo groups with regards to surgical therapy: (1) no operationand (2) surgical resection. The group classified as ‘‘nooperation’’, were defined as no resection of the primarytumor, biopsy only or other diagnostic and palliativeprocedures. The group classified as ‘‘surgically treated’’underwent partial mastectomy (PM), total mastectomy(TM), or modified radical mastectomy. The latter twomastectomy groups were combined into one group for theanalysis, TM. Of the more than 16,000 patients, 6861 did notreceive surgical resection. Patients who underwent surgicalresection totaled 9162 (57.2%); 3513 (38.3%) PM and 5649(61.7%) TM. The 3-year survival for all patients was 24.9%.

The mean survival for the group who did not receive surgicaltherapy was 19.3 months, 26.9 months for those undergoingPM and 31.9 months for those undergoing TM. Independentvariables that affected outcome included surgical resection,administration of systemic therapy, number of metastaticsites and type of metastatic disease. Those variables whichdid not affect outcome included type of surgical resection,tumor size, regional lymph node dissection, or number ofinvolved axillary nodes. Of note, not only did the resectionof the primary tumor provide for a statistically significantsurvival advantage, patients with uninvolved margins afterresection had an increase in 3-year survival (35.7% vs. 26.1%for TM and 34.7% vs. 26.4% for PM). The authors do concedethat it was not possible to control for bias regarding patientselection for surgical resection, however they did attemptto control for this bias by adjusting for number of metastaticsites, type of organ involvement and use of chemotherapyand hormonal therapy.

In 2006, the MD Anderson group published a retrospectivereview of their own data for stage IV breast cancer patientswith intact primary tumors undergoing treatment from 1997to 2002 [40]. Of the 224 patients identified, 82 (37%)underwent surgical resection of the primary tumor while 142(63%) did not receive surgery. Both PM (48%) and mastect-omy (52%) were utilized as surgical procedures. The surgerygroup was defined as those patients who underwentresection within 3 months of being diagnosed with stage IVdisease or at any time during treatment or long-term follow-up for stage IV disease. Patients treated with metastasect-omy were also included. The non-surgery group includedpatients who did not undergo resection at any time. Patientsfrom both groups were treated with some form of systemictherapy. End points for the analysis were overall survival andmetastatic progression-free survival with a median follow-up time of 32.1 months. On univariate analysis, clinicaltumor size, number of metastatic sites and Her2 status weresignificant predictors of overall survival. Multivariate analy-sis identified only two factors significant for overall survival;presence of only one site of metastatic disease and lack ofHer2 gene amplification. There was a trend towardsimproved overall survival in those patients who underwentsurgical resection in both univariate and multivariateanalysis (p ¼ 0.091 and 0.12, respectively). The authors donote that the surgical group and the non-surgical group hadstatistically significant differences. Surgical resection wasmore likely in patients who were younger, were Her2positive, received chemotherapy, had less nodal involve-ment and had a single site of metastatic disease. Theauthors also acknowledge the potential selection biasinherent in this type of retrospective review. To furtherlend significance to this study, the authors performed asecond analysis after removing 11 patients who experiencedcomplete response to systemic therapy of their distantdisease before undergoing surgical resection of the primarysite. Surgical resection of the primary was still significantlyassociated with an improvement in metastatic progression-free survival.

Rapiti et al. retrospectively reviewed 300 metastaticbreast cancer patients recorded at the Geneva CancerRegistry between 1977 and 1996 [41]. Overall, 127 (42%)patients underwent mastectomy (n ¼ 87) or PM (n ¼ 40).The remaining 173 (58%) did not receive any type of surgical

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resection. Negative margins were achieved in the surgicalgroup in 61 (48%) patients, while 33 (26%) had positivemargins and 33 (26%) were unknown. Axillary node dissec-tion was performed only for 73 (57%) of the surgical patientsand the majority of patients undergoing PM did not receiveadjuvant radiotherapy (n ¼ 29). As noted in the MDAnderson study, there were significant differences betweenthose patients who underwent surgery and those who didnot. The surgical patients were more likely to be of youngerage, have smaller primary tumors and were more likely tohave only one site of metastasis. The 5-year breast cancer-specific survival was 27% for women undergoing surgery withnegative margins, 16% for those with positive margins aftersurgery and 12% for women who did not have surgery(p ¼ 0.0002). Clinical characteristics associated with survi-val on univariate analysis included age, regional lymph nodeinvolvement, ER status, number of metastatic sites andpresence of visceral and CNS metastases. Surgical resectionof the primary tumor was also significant in predicting breastcancer-specific survival (p ¼ 0.0003). More importantly,surgical resection with positive margins did not show adifference in cancer-specific survival compared to nosurgical resection. On multivariate analysis age, regionalnode involvement, visceral or CNS metastases and hormonaltherapy remained significant predictors. Local resection ofthe primary tumor also remained as a significant predictor ofcancer-specific survival (p ¼ 0.048). Of note, a subgroupanalysis of patients with bone metastases-only showedsurgery to be associated with a reduced risk of breastcancer death (HR, 0.2; p ¼ 0.001). These authors also notethe possibility of selection bias, but point out that theirsubgroup analyses, in which they attempted to correct forthese biases (short survival, delayed metastatic disease andmore advanced tumors), continued to show a protectiveaffect of surgery for stage IV breast cancer patients.

The most recent support for surgery in stage IV breastcancer comes from the analysis of the 1988–2003 Surveil-lance, Epidemiology and End Results (SEER) data from theNational Cancer Institute [42]. Gnerlich et al. identified9734 patients with stage IV breast cancer and comparedthose who underwent surgery for their primary tumor(n ¼ 4578, 47%) to those who did not (n ¼ 5156, 53%). Ofthe 4578 patients who underwent surgery, 1844 (40.3%) hadpartial mastectomies and 2485 (54.3%) had mastectomies.Again, similar to all the studies mentioned above, therewere significant differences in characteristics betweenthose women who had surgical resection of their primarytumor and those who did not. Women who underwentsurgery were younger, diagnosed earlier in the study period,were more likely to have tumors o5 cm in size and with ERpositive receptor status. Using the year 2003 as the endpointfor analysis, 24% of women who underwent surgery for theirprimary tumor were still alive, compared to 16% of womenwho did not (po0.001). The most conservative estimate forthe relationship between risk of death and surgical resectionof the primary breast tumor revealed that women under-going surgery were 37% less likely to die during the studyperiod. The authors caution that this was an observationalstudy and thus the conclusion that surgery has a directeffect on survival cannot be inferred.

The number of women presenting with stage IV breastcancer and intact primary tumors is small when compared to

the total number of breast cancer diagnoses each year.However, with more than 40,000 breast cancer deathsexpected in 2007, there appear to be a significant number ofwomen who might benefit from aggressive therapy for theiradvanced disease. Both institutional and national serieshave provided evidence that local surgical therapy for theprimary tumor may allow for prolonged survival. Systemictherapy for breast cancer continues to improve, and acomplete clinical response for distant disease is notuncommon. Therefore, it is reasonable to postulate thatsurgical resection of all primary locoregional tumor couldlimit the likelihood of local or systemic recurrence.

Surgery for distant disease

Unlike the treatment algorithm for other metastatic solidtumors, resection of distant sites has not been routinelyoffered to patients with metastatic breast cancer, as it hasnot been thought to affect cure or impact long-termsurvival. However, as previously discussed, improved thera-pies for metastatic breast cancer using polychemotherapeu-tic agents (particularly herceptin, taxanes and aromataseinhibitors) with the resulting improvement in survivalsuggests a more aggressive approach with primary breastsurgery and metastasectomy may be appropriate.

Studies support an improvement in survival over the lastfew decades following diagnosis of metastatic cancer.Giordano et al. evaluated 834 patients treated withrecurrent breast disease over the last 20 years and noted asteady improvement in patient outcome [43]. His studyfound that patients treated from 1974 to 1979 had a mediansurvival of 15 months and a 5-year survival of 10%. However,in the interval period from 1995 to 2000 the median survivalfor patients with metastatic breast cancer was 51 months,with a 5-year survival rate of 40%. Greenberg et al. reportedin 1581 patients treated with metastatic breast cancer that263 patients (16.6%) achieved complete responses, and 49patients (3.1%) remained in remission for more than 5 years[44]. Others [45,46] have reported similar rates of responseto systemic treatment for metastatic breast cancer.

The increased long-term survival for patients withmetastatic breast cancer has caused some clinicians tochallenge the established dogma that patients with meta-static disease are not candidates for surgery with curativeintent. Bathe et al. [47] notes the controversy over differentmodels of growth patterns of breast cancer metastasis. Theconventional paradigm for the development of metastasis iscontinual growth by Gompertzian growth kinetics of smallnumber of micrometastasis (oligometastasis) until recur-rence is clinically apparent. However, model does notexplain how some patients under close observation for longperiods of time suddenly present with extensive bulkyrecurrence. Demicheli and co-workers have proposed analternate ‘‘tumor dormancy model’’ where the micrometas-tasis in the pre-clinical phase may lie quiescent and growthrates may depend on two factors: (1) the removal anangiogenesis inhibitor or (2) the transformation of asubpopulation of tumor cells to angiogenic phenotypeleading micrometastasis to escape dormancy.

Tait et al. provide a clinical framework in support of thismodel [48]. The authors assert that surgical metastasectomy

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Surgery for palliation and treatment of advanced breast cancer 255

in selected cases may be indicated in addition to systemictreatment to achieve a complete response to remove alltumor cells of the angiogenic phenotype, as well as toeradicate chemotherapy-resistant clones. Micrometastaticfoci may become sequestered in ‘‘sanctuary sites’’ notaccessible to chemotherapy allowing a small population ofcells to remain viable. Lee reviewed seven autopsy series ofwomen with metastatic breast cancer and noted anincidence of isolated liver metastasis ranging from 2% to12%, as well as an incidence of isolated pulmonarymetastasis of 4–6% [49]. With the increased sensitivity ofmodern imaging tools, this disease reservoir of asympto-matic metastatic disease will be identified, andthese patients will present as possible candidates formetastasectomy.

Several investigators have presented their experience inpatients undergoing metastasectomy for breast cancer. Eliaset al. reported data on 54 patients with stage IV breastcancer that underwent resection of liver metastasis [50]. Allpatients underwent intra-operative liver ultrasound. In 20(46.7%) patients additional liver metastasis was detectedleading to a resection different than the preoperativeplanned liver resection. Forty-four patients underwent acurative resection and 10 were termed as palliative orincomplete resection. All but two patients received neoad-juvant chemotherapy. Twenty-five patients underwent post-hepatectomy hepatic arterial infusion chemotherapy. In thisseries, overall survival and disease-free survival were at 50%and 42% at 3 years and 34% and 22% at 5 years.

Singletary et al. reviewed eight retrospective studieslooking at primary lung resection for metastatic breastcancer in a total of 744 patients, most of whom weretreated with systemic therapy [51]. Median survival timesranged from 42 to 79 months. The 5-year actuarial survivalranged from 35% to 80%. The 10-year actuarial survivalranged from 8% to 60%. In this reported series, Friedel et al.[52] with the largest number patients at 467 reported amedian survival of 50 months, DFS of 36 months, 5-yearsurvival of 45% and a 10-year survival of 26% followingpulmonary metastasectomy.

Brain metastasis is diagnosed in 10–15% of stage IV breastcancer patients, and in 20% of these patients, this will bethe first site of recurrence. In 1994, Flickinger et al. [53]reported in a multi-institutional study suggested for solitarybrain metastasis, radio-surgery has survival advantages overwhole brain radiation. Jawahar et al. [54] in 2002 noted nosurvival advantage in 103 patients, (11.5% patients had abreast cancer diagnosis) in patients who received radio-surgery alone vs. patient with prior radiation.

These series are retrospective and are therefore prone topatient selection bias, as discussed in the previous section.In addition, few series have well-selected control popula-tions with which to compare outcome in unresectedpatients. Nevertheless, in aggregate, these studies suggesta possible role for metastasectomy in well-selectedpatients.

Summary

The palliative benefits of surgery in patients with stage IVbreast cancer have long been appreciated. Optimizing

patient comfort and quality of life are critically importantgoals in these patients, most of whom have limited lifeexpectancy. Advancements in reconstructive techniqueshave allowed for closure of extensive and complex defectsof the chest wall and surrounding soft tissue without theneed to sacrifice oncologic goals. However, care must betaken to weigh the extent of surgery and reconstructionagainst the possible delay to radiation and systemictreatment, as multimodality therapy offers the best chancefor durable symptom management in these challengingpatients.

The emergence of increasingly effective systemic thera-pies has also created the need to address resectable primarysites as well as distant sites in women with metastatic breastcancer, as many can expect to survive for many years withstable disease. Several models of cancer and metastaticprogression have been proposed. However, the significantchallenge of identifying those patients who may most gainfrom local surgery remains. This question is ideally suited formulti-institutional prospective, randomized controlledtrials, as no single institution alone has sufficient experienceto definitively address these issues. Careful considerationmust be given to incorporating disease extent, sites ofinvolvement, patient comorbidities and rate of progressioninto the study design. Furthermore, genomic and proteomicphenotyping of tumors may in future prove to be importantcriteria for patient selection for ‘‘targeted’’ surgical therapyand must be a fundamental component of these studies. Thenew generation of prospective clinical trials of surgery forstage IV breast cancer patients may identify a subset ofwomen who may benefit from incorporating surgery into amultimodality treatment plan, leading to improved qualityof life, survival and potential cure in women with advanceddisease.

References

[1] Olson JS. Bathsheba’s breast: women, cancer, and history.Baltimore: Johns Hopkins University Press; 2002.

[2] Burstein HJ, Harris LN, Marcom PK, Lambert-Falls R, Havlin K,Overmoyer B, et al. Trastuzumab and vinorelbine as first-linetherapy for HER2-overexpressing metastatic breast cancer:multicenter phase II trial with clinical outcomes, analysis ofserum tumor markers as predictive factors, and cardiacsurveillance algorithm. Journal of Clinical Oncology 2003;21(15):2889–95.

[3] Gori S, Colozza M, Mosconi AM, Franceschi E, Basurto C,Cherubini R, et al. Phase II study of weekly paclitaxel andtrastuzumab in anthracycline- and taxane-pretreated patientswith HER2-overexpressing metastatic breast cancer. BritishJournal of Cancer 2004;90(1):36–40.

[4] Chin PL, Andersen JS, Somlo G, Chu DZ, Schwarz RE, EllenhornJD. Esthetic reconstruction after mastectomy for inflammatorybreast cancer: is it worthwhile? Journal of the AmericanCollege of Surgeons 2000;190(3):304–9.

[5] Behnam AB, Nguyen D, Moran SL, Serletti JM. TRAM flap breastreconstruction for patients with advanced breast disease.Annals of Plastic Surgery 2003;50(6):567–71.

[6] Foster RD, Esserman LJ, Anthony JP, Hwang ES, Do H. Skin-sparing mastectomy and immediate breast reconstruction: aprospective cohort study for the treatment of advanced stagesof breast carcinoma. Annals of Surgical Oncology 2002;9(5):462–6.

ARTICLE IN PRESS

M. Alvarado et al.256

[7] Foster RD, Hansen SL, Esserman LJ, Hwang ES, Ewing C, Lane K,et al. Safety of immediate transverse rectus abdominismyocutaneous breast reconstruction for patients with locallyadvanced disease. Archives of Surgery 2005;140(2):196–8[discussion 199-200].

[8] Parkash S, Srinivasan R, Ananthakrishnan N. Primary closure ofexcisional defects of the breast with local flaps: a problem inthe treatment of advanced carcinoma of the breast indeveloping countries. British Journal of Plastic Surgery 1981;34(3):291–4.

[9] Williams RJ, Fryatt IJ, Abbott WC, White H. Omentaltransposition in the treatment of locally advanced andrecurrent breast cancer. British Journal of Surgery 1989;76(6):559–63.

[10] Cheung KL, Willsher PC, Robertson JF, Bailie FB, Daly JC,Blamey RW. Omental transposition flap for gross locallyrecurrent breast cancer. The Australian and New ZealandJournal of Surgery 1997;67(4):185–6.

[11] Lee SH, Cheah DS, Krishnan MM. Omental transposition flap andsplit skin graft for locally advanced breast carcinoma.Singapore Medical Journal 1990;31(3):217–20.

[12] Apffelstaedt J. Indications and complications of latissimusdorsi myocutaneous flaps in oncologic breast surgery. WorldJournal of Surgery 2002;26(9):1088–93.

[13] Anthony JP, Foster RD. The reconstruction of complex thoracicwounds: a fleur-de-lys modification of the rectus abdominismyocutaneous flap. Plastic and Reconstructive Surgery2001;107(5):1229–33.

[14] Mohamed SA, Sakr MF, El-Hammadi HA, Moussa MM, El-SharakyMM. The use of the ‘TRAM’ flap in some oncological problems.International Surgery 2000;85(4):347–52.

[15] Bogossian N, Chaglassian T, Rosenberg PH, Moore MP. Externaloblique myocutaneous flap coverage of large chest-walldefects following resection of breast tumors. Plastic andReconstructive Surgery 1996;97(1):97–103.

[16] Deo SV, Purkayastha J, Shukla NK, Asthana S. Myocutaneousversus thoraco-abdominal flap cover for soft tissuedefects following surgery for locally advanced and recurrentbreast cancer. Journal of Surgical Oncology 2003;83(1):31–5.

[17] Hidalgo DA, Saldana EF, Rusch VW. Free flap chest wallreconstruction for recurrent breast cancer and radiationulcers. Annals of Plastic Surgery 1993;30(4):375–80.

[18] Tukiainen E, Popov P, Asko-Seljavaara S. Microvascular recon-structions of full-thickness oncological chest wall defects.Annals of Surgery 2003;238(6):794–801 [discussion 801-2].

[19] Sullivan SR, Truxillo TM, Mann GN, Isik FF. Utility of the freedeep inferior epigastric perforator flap in chest wall recon-struction. The Breast Journal 2007;13(1):50–4.

[20] Retsky M, Bonadonna G, Demicheli R, Folkman J, Hrushesky W,Valagussa P. Hypothesis: induced angiogenesis after surgery inpremenopausal node-positive breast cancer patients is a majorunderlying reason why adjuvant chemotherapy works particu-larly well for those patients. Breast Cancer Research2004;6(4):R372–4.

[21] Dauplat J, Le Bouedec G, Pomel C, Scherer C. Cytoreductivesurgery for advanced stages of ovarian cancer. Seminars inSurgical Oncology 2000;19(1):42–8.

[22] Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V,McGrath PC, et al. Nephrectomy followed by interferon alfa-2bcompared with interferon alfa-2b alone for metastatic renal-cell cancer. The New England Journal of Medicine 2001;345(23):1655–9.

[23] Flanigan RC, Yonover PM. The role of resection for patientswith renal carcinoma. Current Oncology Reports 2001;3(5):424–32.

[24] Rosen SA, Buell JF, Yoshida A, Kazsuba S, Hurst R, Michelassi F,et al. Initial presentation with stage IV colorectal cancer: how

aggressive should we be? Archives of Surgery 2000;135(5):530–4 [discussion 534-5].

[25] Cook AD, Single R, McCahill LE. Surgical resection of primarytumors in patients who present with stage IV colorectal cancer:an analysis of surveillance, epidemiology, and end results data,1988 to 2000. Annals of Surgical Oncology 2005;12(8):637–45.

[26] Aoyagi K, Koufuji K, Yano S, Murakami N, Miyagi M, Takeda J,et al. Long-term survival after gastric cancer with livermetastasis: a report of two cases. Kurume Medical Journal2001;48(4):335–8.

[27] Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer andimmune cells: role of STAT3 in the tumour microenvironment.Nature Reviews Immunology 2007;7(1):41–51.

[28] Pardoll D. Does the immune system see tumors as foreign orself? Annual Review of Immunology 2003;21:807–39.

[29] Drake CG, Pardoll DM. Tumor immunology—towards a para-digm of reciprocal research. Seminars in Cancer Biology 2002;12(1):73–80.

[30] Sinha P, Clements VK, Miller S, Ostrand-Rosenberg S. Tumorimmunity: a balancing act between T cell activation, macro-phage activation and tumor-induced immune suppression.Cancer Immunology Immunotherapy 2005;54(11):1137–42.

[31] Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, MillerMC, et al. Circulating tumor cells at each follow-up time pointduring therapy of metastatic breast cancer patients predictprogression-free and overall survival. Clinical Cancer Research2006;12(14 Part 1):4218–24.

[32] Benoy IH, Elst H, Philips M, Wuyts H, Van Dam P, Scharpe S,et al. Prognostic significance of disseminated tumor cells asdetected by quantitative real-time reverse-transcriptase poly-merase chain reaction in patients with breast cancer. ClinicalBreast Cancer 2006;7(2):146–52.

[33] Wong NS, Kahn HJ, Zhang L, Oldfield S, Yang LY, Marks A, et al.Prognostic significance of circulating tumour cells enumeratedafter filtration enrichment in early and metastatic breastcancer patients. Breast Cancer Research Treatment 2006;99(1):63–9.

[34] Braun S, Marth C. Circulating tumor cells in metastatic breastcancer—toward individualized treatment? New EnglandJournal of Medicine 2004;351(8):824–6.

[35] Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, MillerMC, et al. Circulating tumor cells, disease progression, andsurvival in metastatic breast cancer. New England Journal ofMedicine 2004;351(8):781–91.

[36] Feng Y, Sun B, Li X, Zhang L, Niu Y, Xiao C, et al. Differentiallyexpressed genes between primary cancer and paired lymphnode metastases predict clinical outcome of node-positivebreast cancer patients. Breast Cancer Research Treatment2007;103(3):319–29.

[37] Van den Eynden GG, Van Laere SJ, Van der Auwera I, Gilles L,Burn JL, Colpaert C, et al. Differential expression of hypoxiaand (lymph) angiogenesis-related genes at different metastaticsites in breast cancer. Clinical and Experimental Metastasis2007;24(1):13–23.

[38] Woelfle U, Cloos J, Sauter G, Riethdorf L, Janicke F, van Diest P,et al. Molecular signature associated with bone marrowmicrometastasis in human breast cancer. Cancer Research2003;63(18):5679–84.

[39] Khan SA, Stewart AK, Morrow M. Does aggressive local therapyimprove survival in metastatic breast cancer? Surgery2002;132(4):620–6 [discussion 626-7].

[40] Babiera GV, Rao R, Feng L, Meric-Bernstam F, Kuerer HM,Singletary SE, et al. Effect of primary tumor extirpation inbreast cancer patients who present with stage IV disease andan intact primary tumor. Annals of Surgical Oncology2006;13(6):776–82.

[41] Rapiti E, Verkooijen HM, Vlastos G, Fioretta G, Neyroud-CasparI, Sappino AP, et al. Complete excision of primary breast tumor

ARTICLE IN PRESS

Surgery for palliation and treatment of advanced breast cancer 257

improves survival of patients with metastatic breast cancer atdiagnosis. Journal of Clinical Oncology 2006;24(18):2743–9.

[42] Gnerlich J, Jeffe DB, Deshpande AD, Beers C, Zander C,Margenthaler JA. Surgical removal of the primary tumorincreases overall survival in patients with metastatic breastcancer: analysis of the 1988–2003 SEER data. Annals of SurgicalOncology 2007;14(8):2187–94.

[43] Giordano SH, Buzdar AU, Smith TL, Kau SW, Yang Y, HortobagyiGN. Is breast cancer survival improving? Cancer 2004;100(1):44–52.

[44] Greenberg PA, Hortobagyi GN, Smith TL, Ziegler LD, Frye DK,Buzdar AU. Long-term follow-up of patients with completeremission following combination chemotherapy for metastaticbreast cancer. Journal of Clinical Oncology 1996;14(8):2197–205.

[45] Dieras V. Review of docetaxel/doxorubicin combination inmetastatic breast cancer. Oncology (Williston Park) 1997;11(8 Suppl. 8):31–3.

[46] Aapro MS. Combining new agents with anthracyclines inmetastatic breast cancer: an overview of recent findings.Seminars in Oncology 1999;26(1 Suppl. 3):17–21.

[47] Bathe OF, Kaklamanos IG, Moffat FL, Boggs J, Franceschi D,Livingstone AS. Metastasectomy as a cytoreductive strategy fortreatment of isolated pulmonary and hepatic metastases frombreast cancer. Surgical Oncology 1999;8(1):35–42.

[48] Tait CR, Waterworth A, Loncaster J, Horgan K, Dodwell D. Theoligometastatic state in breast cancer: hypothesis or reality.Breast 2005;14(2):87–93.

[49] Lee YT. Breast carcinoma: pattern of metastasis at autopsy.Journal of Surgical Oncology 1983;23(3):175–80.

[50] Elias D, Maisonnette F, Druet-Cabanac M, Ouellet JF,Guinebretiere JM, Spielmann M, et al. An attempt toclarify indications for hepatectomy for liver metastases frombreast cancer. American Journal of Surgery 2003;185(2):158–64.

[51] Singletary SE, Walsh G, Vauthey JN, Curley S, Sawaya R, WeberKL, et al. A role for curative surgery in the treatment ofselected patients with metastatic breast cancer. Oncologist2003;8(3):241–51.

[52] Friedel G, Pastorino U, Ginsberg RJ, Goldstraw P, Johnston M,Pass H, et al. Results of lung metastasectomy from breastcancer: prognostic criteria on the basis of 467 cases of theinternational registry of lung metastases. European Journal ofCardiothoracic Surgery 2002;22(3):335–44.

[53] Flickinger JC, Kondziolka D, Lunsford LD, Coffey RJ, GoodmanML, Shaw EG, et al. A multi-institutional experience withstereotactic radiosurgery for solitary brain metastasis. Inter-national Journal of Radiation Oncology, Biology, Physics1994;28(4):797–802.

[54] Jawahar A, Willis BK, Smith DR, Ampil F, Datta R, Nanda A.Gamma knife radiosurgery for brain metastases: do patientsbenefit from adjuvant external-beam radiotherapy? An18-month comparative analysis. Stereotactic and FunctionalNeurosurgery 2002;79(3–4):262–71.

[55] Surveillance, Epidemiology, and End Results (SEER) Program/www.seer.cancer.govS SEER*Stat Database: Incidence-SEER17 Regs Limited-Use, Nov 2006 Sub (1973–2004 varying),National Cancer Institute, DCCPS, Surveillance ResearchProgram, Cancer Statistics Branch, released April 2007, basedon the November 2006 submission.