Locally Advanced Breast Cancer

Management of locally advanced and inflammatory breast cancer

INTRODUCTION — Locally advanced breast cancer (LABC) constitutes a wide variety of clinical presentations including:

   Large tumors (>5 cm)
   Extensive regional lymph node involvement
   Direct involvement of the skin or underlying chest wall
   Tumors considered inoperable but without distant metastasis (including involvement of the supraclavicular lymph nodes)
   Inflammatory breast cancer (IBC)

In the TNM staging classification, LABC is represented by stage IIIA (T0-N2; T1/2 - N2; T3 - N1/2), stage IIIB (T4, N0-2), and stage IIIC disease (any T, N3). IBC constitutes T4d primary tumor designation, and therefore, stage IIIB disease. The TNM staging classification for breast cancer is presented in detail elsewhere.

The 2002 revision of the TNM staging criteria reclassified ipsilateral supraclavicular lymph node metastasis as LABC (N3 disease) rather than metastatic disease. Such patients can be rendered disease-free with locoregional therapy plus chemotherapy, and their disease-free survival (DFS) and overall survival (OS) are closer to stage IIIB disease rather than stage IV disease at other sites Since most clinical studies referenced in this review were performed before this change took place, women with supraclavicular nodal disease have usually not been included

EPIDEMIOLOGY — Despite its decreasing frequency over the past several decades, LABC remains an important and challenging problem in clinical practice. Although less than 5 percent of breast cancers diagnosed in mammographically screened populations are stage III tumors, LABC represents 30 to 50 percent of newly diagnosed breast cancers in medically underserved populations, both in the United States and in other countries

Primary IBC is relatively rare, accounting for 0.5 to 2 percent of invasive breast cancers. However, because of its aggressive nature, it accounts for a greater proportion of cases presenting with more advanced disease. As an example, 24 percent of 752 women with stage III breast cancer seen at the MD Anderson Cancer Center had IBC. The incidence of IBC is higher in black compared to white women, and it is rare in men. Pregnancy and lactation do not predispose to the development of IBC.

BIOLOGY AND HISTOLOGY OF INFLAMMATORY BREAST CANCER — Primary IBC is a rapidly progressive tumor with a high propensity for early metastatic spread. It is the most lethal form of LABC. As an example, in data collected between 1998 and 2000 from the NCI Surveillance, Epidemiology and End Results (SEER) program, the median survival of women with IBC was significantly worse than for women with noninflammatory LABC (2.9 versus 6.4 years)

The classic histologic finding of IBC on biopsy of affected skin is dermal lymphatic invasion by tumor cells; this can also be seen in areas of skin that are clinically normal. The malignant cells form tumor emboli, which are responsible for both the local signs and symptoms (see below), and the propensity for distant spread. However, dermal lymphatic invasion is not a necessary criterion for the diagnosis of IBC, which is a clinical diagnosis. Affected patients may present with:

   Clinical signs only without dermal lymphatic invasion
   Dermal lymphatic involvement without clinical signs
   Both clinical signs and dermal lymphatic invasion

Some data suggest a worse prognosis for women with both clinical and pathologic features. However, the NCI SEER database series of 3648 women with IBC treated between 1988 and 2000 did not find a statistically significant difference in median survival among women with pathology only, clinical only, or combined clinical plus pathologic findings (median survival 2.3 versus 3 versus 2.9 years, p = 0.058)

Primary IBC is not a specific histologic subtype of breast cancer, but the tumor is most often of the ductal type.

DIAGNOSIS AND STAGING

Clinical presentation — Most LABC are both palpable and visible, although in some cases, the breast is diffusely infiltrated and lacks a dominant mass. Careful palpation of the skin, breasts, and locoregional lymph nodes (axillary, supraclavicular, and cervical) is the initial step in evaluation. Large tumor size, fixation to the chest wall, fixed or matted axillary nodes (clinical N2 disease), or ipsilateral satellite skin nodules connote LABC.

The diagnosis of IBC is a clinical one, and is based upon the characteristic clinical presentation, defined as "... diffuse brawny induration of the skin of the breast with an erysipeloid edge, usually without underlying palpable mass". Patients with de novo IBC (primary disease) typically present with pain and a rapidly progressing tender, firm, enlarged breast. The skin over the breast is warm, and thickened, with a "peau d'orange" (skin of an orange) appearance. The skin color can range from a pink flushed discoloration initially to redness or a purplish hue that seems to represent ecchymosis. At presentation, almost all women with primary IBC have lymph node involvement and approximately one-third have distant metastases

Differential diagnosis — Several conditions may be confused with IBC, leading to potentially preventable delays in diagnosis and treatment. Infectious mastitis and breast abscess, which typically occur in lactating women, are generally associated with fever and leukocytosis. The inflammation that can accompany ductal ectasia is usually localized. Leukemic involvement of the breast may mimic IBC, but the peripheral blood smear is usually diagnostic.

It may be difficult to differentiate IBC from other LABCs or a breast cancer recurrence involving the skin, causing late inflammation. An inflammatory recurrence of a prior noninflammatory breast cancer has been termed secondary IBC. It usually develops on the chest wall at the site of prior mastectomy, but can rarely occur as a distant cutaneous recurrence.

Mammographic findings — Mammography may disclose an obvious tumor mass, large areas of calcification, or parenchymal distortion. Mammographic findings in patients with IBC may include characteristic skin thickening over the breast, with or without a dominant mass. In one series of 92 patients with IBC, an opacity or malignant type microcalcifications were present in 77 and 49 percent of cases, while skin thickening, nipple eversion, or stromal coarsening were observed in 94, 57, and 85 percent, respectively

A core needle biopsy usually establishes the histologic diagnosis. A full thickness skin biopsy is often obtained if IBC is suspected, since a hallmark of this disease is dermal lymphatic invasion by tumor cells.

Clinical staging evaluation — Once the diagnosis is established, the following staging studies are generally recommended

   Complete physical examination, including neurologic examination, to evaluate for potential signs of distant metastatic disease
   Bilateral mammography
   Blood tests, including a complete blood count and liver function tests
   Radionuclide bone scan
   Chest radiograph or chest CT
   CT scan of the abdomen and pelvis

An advantage of chest CT over chest x-ray is that it can also identify skin thickening, diffuse infiltration of the breast, and the presence of lymphadenopathy or thoracic metastases

PET scanning appears to be more sensitive for detection of metastatic disease than other modalities, but its clinical utility is uncertain, particularly since the specificity of PET scanning appears lower than with other imaging modalities. Although breast cancer is a Medicare reimbursable diagnosis for PET scanning, it is unclear whether PET should be incorporated into routine staging maneuvers. This topic is discussed in detail elsewhere.

TREATMENT FOR LOCALLY ADVANCED BREAST CANCER — The bulk of the data that guides treatment of LABC derives from phase II studies or retrospective reviews of single institution experience, rather than controlled randomized trials, although there are some exceptions. While many of the following principles apply equally to patients with locally advanced noninflammatory as well as inflammatory breast cancer, some treatment aspects differ in patients with IBC (eg, the general recommendation for mastectomy rather than breast conserving therapy). Thus, specific issues relevant to the treatment of IBC are presented separately

Overview of the evolution of therapy — Historically, LABCs were considered inoperable either because they were technically unresectable, or within disease categories with an extremely high risk of metastases, local recurrence, and/or death despite aggressive surgical resection. The so-called "grave signs" of Haagenson and Stout included chest wall fixation, skin edema, ulceration, the presence of satellite nodules, inflammatory breast cancer, matted or fixed axillary nodes, supraclavicular node involvement, or ipsilateral arm edema . Fewer than 20 percent of such patients survived beyond five years with surgery alone. Early trials combining radiation therapy (RT) and surgery resulted in markedly improved local control (79 to 89 percent), but only a modest impact on five-year survival (33 to 50 percent).

Based on the concept of breast cancer as a systemic disease at the time of presentation, chemotherapy was introduced into the treatment of LABC in the 1970s. Overview analyses from the Early Breast Cancer Trialists Collaborative Group overview analyses clearly supported the benefit of postoperative adjuvant polychemotherapy for all subgroups of women, while a few randomized trials suggested that the impact on survival in stage III disease was more modest than that seen for earlier stage breast cancer

Although multimodality therapy employing combinations of systemic and locoregional therapy became the treatment of choice by the 1980s, the optimal sequencing of the individual components was not well defined. In general, operable patients tended to undergo surgery first (usually mastectomy) followed by adjuvant chemotherapy with or without RT. If upfront surgery was not feasible due to advanced disease, patients were offered initial chemotherapy or hormone therapy to downstage the tumor, and permit a subsequent mastectomy.

As experience increased, major clinical responses to induction chemotherapy were noted in the majority of patients, and some (3 to 10 percent) were found to have no invasive tumor remaining within the breast or regional nodes at the time of surgery (ie, pathologic complete response, pCR). Moreover, analysis of long-term outcomes showed that a CR to neoadjuvant chemotherapy (particularly a pCR) was associated with significantly higher disease-free survival (DFS) and overall survival (OS) rates as compared to a lesser or no response

These data led to the hypothesis that the early locoregional response to neoadjuvant chemotherapy was a marker of response in distant occult micrometastases, and that it could be used as a surrogate for the overall efficacy of chemotherapy. Whether higher pCR rates that have been achieved by the introduction of more effective chemotherapy regimens will bring about improvements in DFS and OS remains to be demonstrated, and is the focus of ongoing research.

More recently, a major response to induction chemotherapy has allowed breast conserving therapy (BCT) to become possible for women with LABC who would otherwise have been eligible for mastectomy only. Concerns have been raised regarding the potential for higher local recurrence rates in this setting

Neoadjuvant chemotherapy followed by surgery and RT is now emerging globally as the most common approach for LABC, including IBC . Questions persist regarding sequencing and choice of specific chemotherapy regimens, extent of surgery (including the utility of the sentinel node biopsy), and indications for RT. The following sections will address these issues.

Neoadjuvant chemotherapy

Rationale — There are several theoretical advantages for preoperative as compared to postoperative chemotherapy in LABC:

   Preclinical models demonstrate that chemotherapy administered prior to tumor removal is more biologically favorable than postoperative administration.
   Effective preoperative chemotherapy can reduce the size of the primary tumor, thus allowing for breast conserving surgery in women who might not otherwise qualify.
   The presence of a palpable or radiographically measurable mass permits a direct in vivo measure of the sensitivity of the tumor cells to the chemotherapeutic drugs in the regimen. Early identification of drug resistance can prompt the discontinuation of ineffective therapy (thus avoiding unnecessary toxicity), and a change to a potentially more effective regimen. Careful physical examination of the breasts and chest wall following each chemotherapy cycle by the same observer helps with the early identification of nonresponders, and can avoid unnecessary delay in instituting alternative therapy
   Early administration of chemotherapy enables drug delivery through an intact tumor vasculature.

On the other hand, there are also some theoretical disadvantages:

   Fewer than 5 percent of patients with LABC progress while undergoing neoadjuvant chemotherapy. For these patients, as well as those who do not have a major response to induction therapy, local treatment will be delayed.
   Preoperative chemotherapy may induce the development of early drug resistance. This effect needs to be balanced against the early tumor shrinkage experienced by the majority of treated patients.
   Induction therapy may possibly increase the risk for surgical and radiation-related complications, but this is a theoretical concern and not proven

In practice, the advantages of neoadjuvant chemotherapy exceed the disadvantages, and this approach has become the standard of care for women with stage III breast cancer

Clinical response to neoadjuvant chemotherapy — Clinical measurements of breast masses are often used to assess the response to neoadjuvant chemotherapy. Universally accepted criteria for response to therapy are available:

The World Health Organization/International Union Against Cancer (WHO/UICC) criteria that have been used for 20 years define a clinical CR (cCR) as complete disappearance of all clinically detectable disease in the breast or regional lymph nodes. A partial response (PR) requires a >50 percent reduction in the sum of the products of the two longest perpendicular dimensions of measurable tumor deposits. Progressive disease is defined as a >25 percent increase in the sum of the products of the two longest perpendicular dimensions of measurable tumor deposits, or the appearance of new lesions.

More recently, the Response Evaluation Criteria in Solid Tumors (RECIST) criteria were adopted in the evaluation of systemic anticancer treatments, including those administered in the neoadjuvant setting Although the definition for CR is the same as the WHO/UICC, a PR is defined as a 30 percent decrease in the longest dimension of each measurable tumor deposit.

Because of the sometimes substantial interindividual variation among examiners, the same clinician should perform longitudinal assessment of chemotherapy response, if at all possible. Imaging methods, such as mammography or ultrasound (US) are sometimes added to document disease extent more reliably. Other series suggest a utility for MRI, helical CT, and even PET scans for monitoring the response to neoadjuvant therapy, but these additional imaging methods are not routinely used in response assessment.

Depending on disease stage at presentation and the specific regimen used (see below), the overall clinical response rate to neoadjuvant chemotherapy averages 75 percent (range 47 to 100 percent), and the cCR rate is between 8 and 63 percent

Only one-half to two-thirds of cCRs in the breast will be pathologically confirmed CRs (pCRs), while approximately 5 percent of clinical PRs (cPRs) are found to be pCRs (with the residual abnormality mainly attributed to scarring). Thus, the overall pCR rate following neoadjuvant chemotherapy in women with either large operable or locally advanced inoperable breast cancers ranges from 3.5 to 30 percent

Neoadjuvant chemotherapy can also convert clinically apparent axillary nodal disease to pathologically negative (pN0) status in 23 to 38 percent of patients with LABC. The axillary response to neoadjuvant chemotherapy may be a more important predictor of DFS and OS than the response of the primary tumor. Patients with negative lymph nodes after neoadjuvant chemotherapy fare better than those with positive lymph nodes, and the risk of recurrence and death increases in proportion to the number of positive nodes It is not known whether patients with LABC who demonstrate a response to therapy by virtue of having only a few or no involved lymph nodes should receive less local or systemic therapy than they would have received otherwise.

Management of the axillary nodes, including the utility of sentinel node biopsy in clinically node-negative patients, is discussed below

Impact of response on survival — If it is presumed that a complete response locoregionally is reflective of chemosensitivity in occult distant metastatic sites, patients who have a pCR in both the primary breast tumor and axillary lymph nodes after neoadjuvant chemotherapy should have the highest DFS rates. In fact, several studies indicate a correlation between chemotherapy response, amount of residual tumor in the breast and axilla, and relapse-free survival (RFS) as well as OS. Ongoing randomized controlled trials are addressing the issue of whether induction regimens that substantially increase the pCR rate (eg, sequential anthracycline containing regimens followed by taxanes ) are associated with significantly better DFS and OS.

Neoadjuvant versus adjuvant chemotherapy — Several randomized controlled trials of primary systemic therapy for palpable operable breast cancer, several of which have enrolled a minority of women with LABC, have directly compared neoadjuvant with adjuvant chemotherapy. In general, results appear comparable with either approach. Similar conclusions were reached in a meta-analysis of nine trials that randomly assigned women with breast cancer to neoadjuvant or adjuvant systemic therapy. The issue of neoadjuvant chemotherapy for early stage (operable) breast cancer is discussed in detail elsewhere.

One of the major reasons to pursue neoadjuvant as compared to adjuvant therapy is to increase the likelihood of successful breast preservation in women with large tumors. In trials comparing adjuvant versus neoadjuvant chemotherapy that consist mainly of women with large but potentially operable tumors, the use of neoadjuvant therapy has been associated with a significant increase in the rates of BCT in five studies a borderline difference in another and no difference in three. In the positive trials, the absolute differences between the rates of BCT in the neoadjuvant versus adjuvant therapy arms range from 9 to 30 percent. However, some concern has been raised about whether local failure rates are higher in women who required downstaging to be eligible for BCT compared to those who were candidates before chemotherapy. This issue is addressed in detail below

Choice of chemotherapy regimen — Most treatment guidelines recommend an initial anthracycline-containing regimen. Similar to the situation with standard adjuvant chemotherapy, many American trials use doxorubicin and cyclophosphamide (AC), most commonly with fluorouracil (CAF or FAC) In Europe and Canada, epirubicin has been substituted for doxorubicin (FEC), with roughly equivalent results. Other effective anthracycline-based regimens include doxorubicin followed by CMF, and intensive multidrug regimens. The recommended doses and schedules are the same as those used in the adjuvant setting

Taxanes add substantial efficacy to adjuvant chemotherapy, and they are increasingly used for patients with node-positive breast cancer. The two most frequent methods of incorporating taxanes into adjuvant therapy are:

As a cross-over regimen, in which four cycles of single agent paclitaxel or docetaxel follow (or precede) four cycles of an anthracycline-based regimen

As a component of an established anthracycline-based regimen, substituting for an existing older drug (eg, docetaxel, doxorubicin plus cyclophosphamide [TAC] instead of FAC, or doxorubicin plus paclitaxel instead of AC

Emerging data supports a similar degree of benefit from taxanes in the neoadjuvant setting. The efficacy of this approach was shown in preliminary reports of the TAX-301 trial, in which 162 women with large or locally advanced breast cancer underwent four cycles of induction AC plus vincristine and prednisolone (CAVP); responders were then randomly assigned to continue CAVP for a total of eight courses, or switch to four cycles of docetaxel

The number of pCRs in women who received sequential docetaxel was approximately twofold higher (31 versus 15 percent) than in patients who received only CAVP. Moreover, patients who failed to respond to initial CAVP had a cCR rate of 55 percent to subsequent docetaxel monotherapy. The most recent follow-up from this trial, presented at the San Antonio Conference in 2003, suggests a significant five-year OS benefit for women who received four cycles of CAVP followed by sequential docetaxel compared to those who received CAVP alone (97 versus 78 percent, respectively)

Several questions remain unanswered regarding taxanes as neoadjuvant treatment:

It is uncertain whether sequential or simultaneous administration of anthracyclines and taxanes is more effective. The superiority of sequential treatment was suggested in a trial in which 913 women with untreated operable (T2-3, N0-2 M0) breast cancer were randomly assigned to four 14 day cycles of growth factor-supported dose-intense doxorubicin (50 mg/m2) plus docetaxel (75 mg/m2) or four courses of standard AC followed by four courses of single agent docetaxel (100 mg/m2 every 21 days). Sequential therapy was associated with a twofold higher pCR rate (14 versus 7 percent).

Thus, when taxanes are added to induction chemotherapy, sequential administration of anthracyclines and the taxane is preferred.

It is also unclear whether the status of the axillary nodes can be used to select women with LABC for taxane treatment (ie, reserving taxanes for those with node-positive disease), either using conventional doses, or dose-dense treatment strategies.

Is there a role for trastuzumab? — Approximately 20 percent of human breast cancers have amplified and/or overexpressed HER-2/neu (c-erbB-2), a gene which encodes a cell surface growth factor receptor.

Trastuzumab (Herceptin®) is a humanized monoclonal antibody that binds to a specific epitope of the HER-2/neu protein; it represents a novel approach to breast cancer treatment using mechanisms not exploited by conventional chemotherapy agents.

Multiple doses can be given safely both alone and in combination with other chemotherapeutic agents. Most of the available data are in patients treated for metastatic disease

Initial reports using neoadjuvant trastuzumab with either paclitaxel or vinorelbine for women with HER-2 neu-overexpressing tumors are encouraging. This approach should still be considered investigational at present since data on long-term outcome and safety are lacking.

However, in view of the emerging data showing a significant survival benefit for adding trastuzumab to cytotoxic chemotherapy in the adjuvant treatment of women with high-risk, HER-2/neu-overexpressing earlier stage breast cancer, the addition of postoperative trastuzumab (concomitant with taxane therapy for a total of 12 months of monotherapy) should be strongly considered in patients with HER-2-positive breast tumors.

Duration of neoadjuvant chemotherapy — The optimal duration of induction chemotherapy has not been established in randomized controlled trials. Limited information from clinical reports suggests that the pace of response to neoadjuvant chemotherapy is variable. Some patients achieve maximal tumor reduction after only one or two cycles, while others require up to eight months of therapy

Until the appearance of taxanes, most clinicians administered neoadjuvant chemotherapy (usually anthracycline-based) for a minimum of three to four cycles, with additional courses of the same regimen administered until reaching a "plateau" of maximal clinical response. Chemotherapy was frequently continued for two cycles beyond this clinical endpoint, after which local therapy was recommended. This approach was felt to maximize the rate of complete remission. however, as noted above, emerging data suggest that both responders and nonresponders to an initial anthracycline-based regimen benefit from crossover to an alternate, non cross-resistant therapy, most frequently a taxane.

Consensus recommendations — In view of these early results, a 2003 consensus conference on neoadjuvant chemotherapy for breast cancer recommended the following approach to induction chemotherapy:

   Four cycles of an anthracycline-based regimen or a taxane followed by reassessment of response (see below).
   If there has been a complete or nearly complete clinical response to induction therapy, definitive local treatment is appropriate.
   Patients with a lesser response could be considered for four additional cycles of a non cross-resistant drug or drugs (eg, a taxane if an anthracycline regimen was initially administered, or vice-versa).
   As with adjuvant therapy, eight total cycles of adjuvant therapy are recommended. They may all be administered preoperatively, or split between induction and postoperative therapy.
   In the absence of progressive disease, at least two and preferably four cycles of chemotherapy should be given before concluding that patients are "nonresponders".

Neoadjuvant hormone therapy — Neoadjuvant hormone therapy (NAHT) is an acceptable option for selected patients with estrogen receptor (ER)-positive breast cancer, although the likelihood of a pathologic complete response (pCR) appears to be lower than with systemic chemotherapy. In contrast to neoadjuvant chemotherapy, the correlation between response to NAHT and disease-free survival (DFS) and overall survival (OS) has not been established in prospective trials. Also, the extent to which rates of breast conservation therapy (BCT) are increased with NAHT is unclear.

Tamoxifen — Neoadjuvant tamoxifen decreases overall tumor volume in approximately one-half of LABCs. The frequency of a pCR after tamoxifen is not well studied, but appears to be low, approximately 5 percent.

The efficacy of neoadjuvant tamoxifen was illustrated in a trial in which 47 ER-positive women with LABC who were over the age of 75, or who had substantial comorbidity received 3 to 6 months of tamoxifen (20 mg daily) prior to surgery. The clinical complete (cCR) and overall response rates were 6 and 47 percent, respectively. Although 29 patients (62 percent) were rendered free of disease following surgery, BCT was only possible in five. The estimated progression-free survival (PFS) and OS rates were 50 and 83 percent at 2 years, and 41 and 59 percent at 5 years, respectively.

Since responses tend to occur gradually, treatment for 3 to 6 months (in the absence of progression) is necessary before concluding that the disease is unresponsive.

Aromatase inhibitors — Increasingly the aromatase inhibitors (AIs) are being used for NAHT. In one representative trial, 24 postmenopausal women with locally advanced or large (>3 cm) ER-positive primary breast cancer were randomly assigned to one of two doses of anastrozole (1 mg or 10 mg) daily for three months. At baseline, only three patients had T3/T4b disease; the remainder had T2 lesions. The median reduction in tumor volume over 12 weeks was 70 to 80 percent, and 15 of 17 who would otherwise have required mastectomy were able to undergo BCT. Survival data were not reported.

Although the data are limited, women whose tumors overexpress HER-2/neu may preferentially benefit from NAHT with an AI compared to tamoxifen

In one trial, 250 postmenopausal women who were ineligible for BCT were randomly assigned to four months of preoperative letrozole (2.5 mg daily) or tamoxifen (20 mg daily). Women receiving letrozole had a significantly higher objective response rate (60 versus 41 percent), and were also more likely to undergo subsequent BCT (48 versus 36 percent). The difference in response rates was particularly marked in women with erbB-1 or HER-2/neu-positive tumors (88 versus 21 percent for letrozole and tamoxifen, respectively).

The IMPACT trial randomly assigned 330 women with ER-positive breast cancer to three months of preoperative anastrozole, tamoxifen or both. While there were no significant differences in objective response or the rate of BCT in the three groups, the clinical response rate was significantly higher with anastrozole in those with HER-2-positive tumors (n = 34, 58 versus 22 percent).

While these early results are encouraging, it is premature to judge whether the overall benefit of the exceedingly low estrogen levels that are achieved with AIs will outweigh potential long-term toxicities (eg, bone loss). Further research in survivors is necessary to answer this question. The benefits and side effects of AIs are discussed elsewhere. (

Summary — NAHT is an effective approach for women with LABC, but may be best reserved for elderly women with impaired organ function, patients who are unwilling to accept chemotherapy-related toxicity, or those with a poor performance status or who are felt to have unacceptably high surgical risk. Other patients with ER-positive LABC, and most with larger operable tumors are best treated with combined chemotherapy and hormone therapy.

If NAHT is used, response should be assessed at the end of three months, unless there is clear evidence of tumor progression. If the tumor is responding or stable, treatment should be continued for at least 6 months

Induction chemoradiation — Concurrent radiation therapy (RT) and chemotherapy has only rarely been applied to patients with LABC because of concerns about radiosensitization with anthracyclines. The efficacy of taxanes has prompted a reevaluation of the benefits of initial chemoradiotherapy

In a prospective trial, 44 women with stage IIB or III breast cancer received twice weekly paclitaxel (30 mg/m2 over one hour) concurrent with RT (45 Gy, delivered in daily 1.8 Gy fractions), followed by mastectomy and more chemotherapy. The overall clinical response and pCR rates were 91 and 16 percent, respectively. Treatment was well tolerated, with grade 3 skin desquamation and stomatitis during induction therapy in 7 and 2 percent of patients, respectively. As long-term results are not yet available, this treatment approach should only be considered as part of a clinical trial.

Local therapy — Following induction chemotherapy, the options for local therapy are surgery (mastectomy or BCT), RT, or both. In general, assessment of tumor response (ie, extent and site(s) of residual disease) after induction chemotherapy usually drives locoregional management recommendations. After neoadjuvant therapy, a careful physical examination with measurements to document the extent of residual disease in the breast and regional lymph nodes should be accompanied by repeat imaging studies (mammography, ultrasound, and/or MRI).

Surgery versus RT — The risk of locoregional recurrence in women with LABC who are treated with surgery or RT alone is approximately 30 to 50 percent. Randomized trials comparing total mastectomy to RT alone suggest similar local failure and survival rates:

In one trial, 132 women with LABC were randomly assigned to mastectomy or RT following three courses of doxorubicin and vinblastine. Seven cycles of the same regimen were administered postoperatively. Although a higher proportion of women were rendered disease-free after mastectomy compared to women given RT (100 versus 60 percent), the total response rate at the end of therapy was identical (75 percent). There were no significant differences in patterns of treatment failure, response duration, or median OS.

In the second study, 91 women with stage III breast cancer who were considered operable following neoadjuvant chemotherapy were randomly assigned to mastectomy or RT. After locoregional treatment, both the overall response (100 versus 77) and cCR rates (100 versus 52 percent) were significantly better with surgery, but local and distant failure rates were comparable (19 versus 27 percent, and 26 versus 23 percent, respectively), as was median OS.

Postoperative RT — In most uncontrolled series and at least one randomized trial, local control rates appear higher when both surgery and RT are included in the treatment strategy even for women who have a pCR to neoadjuvant chemotherapy. However, whether survival is impacted is unclear.

These issues were illustrated in an ECOG trial that randomly assigned 332 women with LABC who were progression-free after six courses of neoadjuvant chemohormonal therapy to surgery alone or followed by RT. With over nine years of follow-up, time to relapse and OS were similar in both treatment arms. However, the isolated locoregional failure rate was significantly lower in patients who received RT compared to those who either refused treatment, or were assigned to surgery alone (4 versus 27 and 20 percent, respectively). Some concerns have been raised regarding the methodology used in this study.

On the other hand, a survival benefit for postoperative RT was suggested in a retrospective series from MD Anderson that compared the outcomes of 542 patients treated on six consecutive institutional prospective trials of chemotherapy followed by surgery and RT with those of 134 patients treated on these protocols but without postoperative RT. Irradiated patients had a significantly lower rate of 10-year locoregional recurrence (11 versus 22 percent), and cause-specific survival was also significantly better for those with stage IIIB disease, clinical T4 tumors, or 4 positive nodes.

Controlled trials have not been performed to establish whether all patients with LABC require both RT and surgery. However, limited data based upon retrospective analysis suggest that for patients with a cCR to induction chemotherapy, RT alone is associated with a higher incidence of local recurrence, but not inferior survival.

Although the role, techniques, fields, and doses of RT after neoadjuvant chemotherapy are still undefined, the following is a reasonable approach:

Patients who achieve a pCR in the primary tumor and the axillary nodes, and who either undergo lumpectomy or mastectomy receive RT to the breast and/or chest wall, supraclavicular and/or internal mammary areas.

For those who achieve only a partial response in the primary or who have residual positive lymph nodes, comprehensive RT should include axillary fields.

These recommendations are based on not knowing the original pathologic tumor size or the total number of positive nodes.

BCT after neoadjuvant chemotherapy — Clinical trials provide convincing evidence that 50 to 90 percent of women with LABC can be successfully treated with BCT after neoadjuvant chemotherapy when they otherwise might not qualify. BCT is not an appropriate option for all women, even if they appear to have achieved a major clinical response. Patients must have responded to the extent that skin involvement has regressed, and chest wall fixation, if initially present, has disappeared. Breast MRI is often helpful in determining whether the residual tumor is of limited extent and amenable to wide excision

Of some concern, local failure rates may be higher in women who require downstaging to be eligible for BCT compared to those who were candidates before chemotherapy, or to women undergoing neoadjuvant chemotherapy followed by mastectomy In one series of 257 women with T1 to T3 breast cancer treated with induction chemotherapy followed by lumpectomy and RT, the local recurrence rates were 16 and 22 percent at 5 and 10 years, respectively. In comparison, the 5 and 10 year local recurrence rates for a cohort of patients receiving chemotherapy followed by mastectomy at the same institution were 6 and 12 percent, respectively.

On the other hand, others do not report an increase in locoregional recurrence in women undergoing BCT after neoadjuvant therapy, even for those presenting with locally advanced T3 or T4 disease (but not inflammatory breast cancer), providing surgery is included as a component of local therapy, and nodal involvement is not advanced (ie, clinical N2 or N3) at diagnosis . In contrast to noninflammatory breast cancer, most authorities specifically recommend against BCT in women with IBC

A prognostic index to estimate the likelihood of an in-breast or locoregional tumor recurrence was developed from a series of 340 patients undergoing BCT after neoadjuvant chemotherapy for noninflammatory LABC. One point was assigned for each unfavorable characteristic:

   Clinical N2 or N3 disease
   Residual pathologic tumor size >2 cm
   Multifocal residual disease
   Lymphovascular space invasion

Five-year rates of in-breast recurrence-free survival (RFS) were 97, 88, and 82 percent for patients with 0-1, 2, and 3-4 points; the corresponding values for locoregional RFS were 94, 83, and 58 percent, respectively. Women with three or four of these characteristics may benefit from alternative local treatment strategies or participation in clinical trials of novel local therapies.

If BCT is contemplated, special attention should be paid to tumor localization before starting neoadjuvant chemotherapy, so that the original tumor site can be located if a complete CR is achieved to neoadjuvant chemotherapy. This can be accomplished by inserting a radioopaque clip into the central portion of the tumor under ultrasound guidance prior to any systemic therapy. If necessary, the clip can be needle-localized prior to local therapy.

Axillary staging — Regional nodal status impacts prognosis, and the choice of therapy. The timing of, and best method for assessment of the locoregional nodes is controversial in patients presenting with LABC.

The majority of patients with LABC have palpable nodal disease, and in some cases it is advanced (ie, N2/3). For the minority who are clinically node-negative (N-), assessment of locoregional nodes is often considered prior to therapy, particularly if this information will impact upon the choice of which induction regimen to use (ie, taxane versus non-taxane, dose-dense versus standard schedule) or influence locoregional management.

Some clinicians advocate assessing axillary nodal status by ultrasound-guided fine needle aspiration biopsy (FNA) or core needle biopsy prior to initiation of neoadjuvant therapy

Sentinel lymph node (SLN) mapping and biopsy (SLNB) has been integrated into the care of patients with early stage, clinically N- breast cancer, despite the paucity of randomized trials proving the equivalent oncologic outcomes of SLNB compared to full axillary node dissection (ALND).

Most studies have restricted SLNB to T1 or T2 breast tumors <5 cm. As a result, there are insufficient data on the utility of SLNB in women with larger tumors or IBC. Guidelines from ASCO recommend against the routine use of SLNB for tumor size >5 cm, T4 primaries (ie, skin and/or chest wall invasion), or IBC However, in our view, despite the lack of data, SLNB is a reasonable option prior to instituting neoadjuvant systemic therapy for a T3 tumor as long as the axilla is clinically negative.

For patients undergoing neoadjuvant therapy for a T3 clinically node-negative tumor, the timing of SLNB (ie, prior to or after systemic therapy) has engendered much debate; there is no consensus as to the best approach. We recommend performing SLNB prior to neoadjuvant therapy, because of the impact of the number of positive nodes on the decision to recommend postmastectomy RT, and the influence on radiation field planning. If the SLN is negative, ALND is not performed at the time of surgery; instead, the axilla is irradiated. If the SLN is positive, an ALND is done at the time of surgery, and the axilla and supraclavicular nodes are irradiated only if the nodes are persistently positive.

Others consider that the prognostic information obtained by axillary staging after neoadjuvant therapy is equivalent or superior to that gained prior to treatment, since it permits an assessment of the response to chemotherapy. However, it is not known whether patients who respond to therapy by virtue of having only a few or no involved nodes should receive less local or systemic therapy than they would have received otherwise. ASCO guidelines suggest that if the prognostic information gained from examination of the axillary nodes is deemed valuable for planning local-regional treatment for an individual patient, that SLNB be considered before the institution of systemic therapy

Prognosis — Long term survival can be obtained in approximately 50 percent of women with LABC who are treated with a multimodality approach. Prognostic factors include age, menopausal status, tumor stage and histologic grade, clinical response to neoadjuvant therapy, and ER status. Of these, the most important are response to neoadjuvant therapy, and nodal status

Management of nonresponders — Failure to respond to neoadjuvant chemotherapy is a poor prognostic sign, particularly if disease progresses during therapy. Only approximately one-third remain free of distant disease with multidisciplinary locoregional management

Chemotherapy with a non cross-resistant regimen (eg, taxanes in women who progress during anthracycline-based therapy) is the preferred option. Surgery should only be attempted if a macroscopically complete resection can be accomplished. Patients who remain inoperable should receive locoregional RT with subsequent surgery, if feasible . Hormone therapy is appropriate for patients whose tumors are ER-positive.

TREATMENT OF INFLAMMATORY BREAST CANCER — Inflammatory breast cancer (IBC, stage T4d) is an aggressive form of LABC. As in noninflammatory LABC, single modality therapy is associated with a poor outcome The five-year survival rate with radical or simple mastectomy alone is 10 percent. In a series from the Joint Center for Radiation Therapy using definitive RT only, five-year RFS and OS rates were 17 and 28 percent, respectively. RT in conjunction with surgery provides enhanced locoregional control, but no impact on survival.

In general, women with IBC are approached similarly to those with noninflammatory LABC. However, there are some exceptions. Breast conservation therapy is generally considered inappropriate for these women, as is SLN biopsy.

Combined modality treatment — Many reports emphasize the benefit of the multimodality approach in the management of IBC The benefit of chemotherapy was illustrated in a single institution retrospective study of 179 women with nonmetastatic IBC; 33 received definitive RT, 25 surgery plus RT, 35 chemotherapy and RT, and 86 trimodality therapy. The five-year DFS rates were 40 percent for those undergoing trimodality therapy, 24 percent for those undergoing surgery plus RT, and 6 percent for those undergoing surgery or RT alone. Ten-year DFS rates were 35, 24, and 0 percent, respectively. Locoregional failure rates were significantly higher in patients who did not undergo surgery as part of their treatment (70 versus 19 percent)

The benefit of combined modality treatment has been confirmed in prospective studies; most have used systemic combination chemotherapy initially, but differed in the types and duration of chemotherapy, and the modality used for local therapy. The following illustrates the range of findings:

   The number of patients who obtain a complete (CR) or partial response (PR) to induction chemotherapy is 60 to 80 percent . In patients undergoing postchemotherapy mastectomy, the pathologic CR rates range from 7 to 44 percent.
   Five-year disease-free survival (DFS) rates in patients treated with chemotherapy followed by surgery and RT range from 22 to 49 percent and the overall survival from 30 to 70 percent. Approximately 30 percent of patients with IBC and regional stage IV breast cancer are alive and free of disease at 20 years of follow-up.
   As with other LABC, patients who obtain a rapid and complete remission from chemotherapy have a better prognosis and longer survival than do those with an incomplete response to induction therapy. As an example, in one retrospective report, 61 patients received three cycles of doxorubicin-based induction chemotherapy followed by surgery, RT, and additional chemotherapy Clinical complete and partial responses were achieved by 16 and 45 percent, respectively. For complete responders, partial responders and the entire group, the five-year actuarial DFS was 70, 35, and 27 percent, while locoregional control rates were 89, 68, and 58 percent, respectively.

Optimal chemotherapy regimen — The optimal chemotherapy regimen is unclear. Most series utilize anthracycline-based induction therapy, such as FAC or FEC. Some but not all series suggest a survival benefit for these regimens compared to regimens without an anthracycline.

Although the available data are limited, taxanes appear to add to the efficacy of neoadjuvant chemotherapy in patients with IBC, as they do in women with noninflammatory LABC. In one series of 44 patients with IBC,16 had to be crossed over from an anthracycline-based induction chemotherapy regimen to single agent paclitaxel because of a less that partial clinical response. Seven (44 percent) were subsequently able to undergo mastectomy.

A later report by these same investigators included 240 women with IBC who were treated on six consecutive induction chemotherapy protocols (four using anthracycline-based chemotherapy alone, and two using sequential FAC and paclitaxel). Although the objective response rates were similar in the two groups (74 and 82 percent, respectively), median survival was significantly better in women receiving paclitaxel (54 versus 32 months). Although these data are encouraging, they are not from a randomized controlled trial, and thus must be interpreted cautiously.

The combined local approach of surgery and RT provides optimal locoregional control, but appears to have no impact on OS

Role of postoperative chemotherapy — It has been argued that postoperative chemotherapy is an integral part of treatment for IBC. However, it is unclear whether it is preferable to administer maximal doses of chemotherapy prior to local therapy, when the therapeutic response can be easily assessed, or if better (or perhaps worse) results follow the combined use of preoperative plus postoperative chemotherapy Moreover, there are no data that either support or refute the benefit of postoperative chemotherapy in patients who have a less than adequate response to primary chemotherapy.

Conclusive data on this topic may be available with maturation of data from NSABP trial B-27 and from the European Cooperative Trial in Operable Breast Cancer Until then, a 2003 consensus conference on the use of neoadjuvant chemotherapy in breast cancer made the following recommendations

   Outside of a clinical trial, a total of eight cycles of neoadjuvant chemotherapy should be offered, four of an anthracycline-containing regimen, and four of a taxane-containing regimen.
   If all eight cycles are administered prior to locoregional therapy, there is no demonstrated gain from additional postoperative chemotherapy.
   If only four cycles are administered prior to locoregional therapy, it is reasonable to administer the other four afterward.

Nonsurgical approach — Some reports suggest higher locoregional failure rates when surgery is not a component of therapy for IBC. As an example, in the report of 179 patients noted above, locoregional control was significantly better in women who underwent surgery as part of their multimodality treatment for IBC (76 versus 30 percent)

However, at least two contemporary series question the necessity of mastectomy. In the first, from the Institute Gustave Roussy (France), alternating RT and chemotherapy were administered to 125 women with IBC. Eight cycles of CAFVM chemotherapy (doxorubicin, cyclophosphamide, 5-FU, vincristine, methotrexate) were alternated with three courses of locoregional RT (total dose 65 to 70 Gy). Five year overall and DFS rates were 50 and 38 percent, respectively, and the cumulative rates of local failure and distant metastases were 27 and 53 percent, respectively. These results seem comparable to those achieved with mastectomy plus RT.

Similar results were noted in a report from the Royal Marsden Hospital. Of the 45 women with IBC who achieved a clinical CR to initial chemotherapy, 35 then underwent RT alone while the remainder had surgery plus RT. In the group treated with RT alone, durations of median PFS and OS were 16 and 35 months, respectively. Of the 69 percent who relapsed, one-half relapsed locally. In the surgically treated patients, the median PFS and OS were similar: 20 and 35 months, respectively, and more than one-half relapsed locally. Thus, the addition of mastectomy did not appear to add benefit for either local control or survival.

Nevertheless, we still consider mastectomy to be an integral component of therapy for most women with IBC, if it is feasible after neoadjuvant chemotherapy.

Role of accelerated fractionation RT — The value of hyperfractionated accelerated RT has been evaluated as a means of improving locoregional control. In one series, 39 patients undergoing multimodality treatment for IBC between 1986 and 1993 received twice daily fractions of 1.5 Gy to a total dose 66 Gy. When treatment results were compared to historical controls treated between 1977 and 1985 with 60 Gy conventional fractionation RT, there appeared to be a significant improvement in the rate of locoregional control in favor of the accelerated fractionation group (from 84 versus 58 percent) and in overall survival (77 versus 58 percent).

In a second report, the same RT dose and fractionation scheme (66 Gy in twice daily 1.5 Gy fractions) was alternated with CAFVM polychemotherapy in 53 women with IBC. A CR and PR was achieved by the end of therapy in 83 and 13 percent, respectively, while 4 percent progressed during therapy. With a median follow-up of 39 months, the three- and five-year OS rates were 66 and 45 percent, respectively; and the corresponding DFS rates were 45 and 36 percent, respectively.

While these preliminary data are promising, standard fractionation RT remains the standard of care.

High dose therapy with hematopoietic stem cell support — As noted above, with the introduction of combined modality treatment, approximately 30 percent of patients with IBC are alive and free of disease at 5 years. The main reason for treatment failure is lack of systemic control, a fact that has led to the development of high dose chemotherapy regimens, often with autologous stem cell support.

Unfortunately, despite several years of study, the benefit of this approach is not yet established in patients with IBC. In general, higher objective and pathologic response rates have been obtained using high dose chemotherapy with autologous stem cell support as a component of combined modality therapy, but there have been no dramatic improvements in either disease-free or overall survival. Moreover, this approach is associated with markedly increased toxicity and worse quality of life compared to standard dose chemotherapy.

Thus, high-dose chemotherapy with hematopoietic stem cell support cannot be considered a standard approach to patients with LABC, including IBC. It should only be considered in the context of a clinical trial.

SUMMARY AND RECOMMENDATIONS —

   Combined modality therapy utilizing induction chemotherapy followed by locoregional therapy, including surgery and/or RT is the standard of care for LABC, including IBC. Following neoadjuvant chemotherapy, surgery is recommended, if feasible, followed by RT.

   Breast conserving therapy is not an appropriate option for women with inflammatory breast cancer.

   Anthracycline-based combination chemotherapy is preferred initially, followed sequentially by a taxane

   Any of the regimens that are effective in the adjuvant setting (eg, four cycles of AC followed by four courses of paclitaxel, administered either in standard doses or as a dose-dense regimen with hematopoietic growth factor support) are appropriate choices

   For chemotherapy nonresponders, and those who remain inoperable after neoadjuvant chemotherapy, RT is recommended, followed by surgery, if feasible.

   For women with hormone receptor-positive breast cancer, we recommend that adjuvant hormone therapy be administered following systemic chemotherapy and locoregional therapy.

   For women with HER-2-positive breast tumors, a course of postoperative trastuzumab should be strongly considered, initially with a taxane, and then as monotherapy, to complete 12 months of treatment.