10 Locally Advanced Breast Cancer S. EVA SINGLETARY, MD, FACS Integration of systemic chemotherapy and/or hormonal therapy with surgery and irradiation is considered the standard of care in the treat- ment of locally advanced breast cancer (LABC). Because the greatest risk for patients with LABC is the development of distant metastases and subsequent death, the goals of surgery are to provide maximal locoregional control with minimal disfigurement and to per- mit accurate staging to determine prognosis. Breast conservation surgery is sometimes pos: sible after tumor downstaging with induction chemotherapy, but close cooperation between the medical and surgical oncologists and the radiation therapist is required to determine the feasibility of this option. Similarly, the surgeon must be familiar with the natural history of LABC to assess the advisability of major resec- tions of either persistent advanced primary disease or locoregional recurrences. If life expectancy is very short, as is the case with patients who have bulky visceral disease or ‘metastases nonrespondent to multiple chemo- therapy regimens, the true benefit of a complex but technically feasible operation should be evaluated carefully. However, in selected patients with advanced disease, surgery may achieve quality palliation of local symptoms of pain, hemorrhage, and malodorous ulceration. This chapter defines LABC and addres the role of surgery after tumor downstaging with induction chemotherapy, the use of mas tectomy for inflammatory breast cancer, the feasibility of immediate reconstruction in selected patients with LABC, and recent inno- vations in systemic therapy. DEFINITION OF LOCALLY ADVANCED BREAST CANCER Locally advanced breast cancer generally refers to large primary tumors (> 5 em) associated with skin or chest-wall involvement or with fixed (matted) axillary lymph nodes (T3/T4; N2/N3).! In the most recent TNM staging sys tem,!tumors associated with disease in the ips lateral supraclavicular nodal basin have been eliminated from the LABC category because the supraclavicular basin lies outside the pri- mary lymphatic drainage pathways of the axilla and internal mammary nodes; tumors associ- ated with supraclavicular disease have been reclassified as stage IV disease. However, as patients with distant metastases confined to supraclavicular nodes have a better prognosis than patients with metastases at other distant sites and can be rendered disease free with locoregional therapy?metastases limited to the ipsilateral sub- or supraclavicular fossa will be included in the definition of LABC offered here. Large primary tumors (> 5 cm) with no evidence of nodal involvement (T3;NO) have a ‘more favorable prognosis than LABC, with a S- year survival rate of 70 to 80 percent; thus, in ‘the most recent TNM staging system, T3NO lesions have been reclassified as stage IIB dis- ease. However, as most series have classified T3NO lesions as LABC for the purposes of 153Isd BREAST CANCER treatment, these tumors will also be included in the present definition of LABC ROLE OF SURGERY AFTER INDUCTION CHEMOTHERAPY Since the mid-1970s, patients with LABC treated at The University of Texas M. D. Ander- son Cancer Center have received three to four cycles of doxorubicin-based combination chemotherapy prior to local therapy; local ther- apy is followed by the completion of systemic therapy and irradiation. Between 1974 and 1996, patients with LABC were treated in four trials addressing four major concerns about the use of induction chemotherapy: (I) whether tumor progression will occur during induction chemotherapy, rendering the tumor unre- sectable even with radical surgery; (2) whether operative morbidity is increased after induction chemotherapy; (3) whether the histologic stag- ing information obtained from the surgical specimen after induction chemotherapy main- tains its prognostic correlations with survival; (4) and whether breast conservation therapy with or without an axillary node dissection is feasible and safe in patients with LABC. In the first clinical trial at M. D. Anderson Cancer Center (1974 to 1985), induction combi- nation chemotherapy was administered to 174 evaluable patients (191 registered) with nor flammatory stage III breast cancer? After three cycles of S-fluorouracil, doxorubicin, and cyclophosphamide (FAC), patients with an excellent tumor response underwent irradiation of the chest wall and regional lymph nodes. Patients with a substantial volume of residual tumor underwent mastectomy and irradiation, Afier completion of locoregional therapy, FAC \was reinitiated and continued until a dose of 450 mg/m? of doxorubicin was reached. Then treat- ment with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was instituted and continued fora total treatment period of 2 years After the three cycles of induction chemo- therapy with FAC, 17 percent of patients had a complete response (no evidence of tumor by physical or radiographic examination). Seventy- one percent had a partial response (= 50 percent tumor shrinkage), Only 10 percent had a minor or no significant response to induction chemo- therapy. Tumor progression occurred in 2 per cent of patients, This trial demonstrated that the ‘majority of patients will have significant tumor shrinkage with induction chemotherapy and that the likelihood of tumor progression is low. As the virulence of a tumor is associated with chemoresistance, tumors that progress during aggressive chemotherapy are unlikely to be controlled with surgery, and a crossover chemotherapy regimen should be considered. This study also confirmed that induction chemotherapy is well tolerated and that surgical procedures after induction chemotherapy can be completed without an increased rate of infection or delayed wound healing ‘The above trial refuted the concept that histo- logic staging information obtained afier induc- tion chemotherapy would not have predictive power. The histologically confirmed response in the mastectomy specimen after induction chemotherapy was an excellent prognostic fac- tor for survival and was more accurate than clinical assessment of response.56The number of positive axillary nodes after induction chemotherapy also remained prognostic for survival: actuarial S-year survival rates were 70 percent for patients with negative lymph nodes, 62 percent for patients with one to three posi tive lymph nodes, 47 percent for patients with four to ten positive lymph nodes, and 21 per cent for patients with more than ten positive lymph nodes. The 5-year disease-free survival rates were 72, 46, 35, and 6 percent, respec- tively. When the subsets of patients with four or ‘more positive lymph nodes were combined, the overall survival rate at 5 years was 38 percent, and the disease-free survival rate dropped to only 20 percent. As patients with four or more positive lymph nodes after induction chemo- therapy have a survival rate similar to that obtained in historical trials of mastectomy andpostoperative irradiation without systemic ther- apy2” these patients should be considered for innovative clinical trials The second M. D. Anderson clinical trial (1985 to 1989) was designed to determine whether the extent of residual disease in the ‘mastectomy specimen after induction chemo- therapy can be used as a guide in planning p operative adjuvant therapy. Three cycles of ristine, doxorubicin, cyclophosphamide, and prednisone (VACP) were administered at 21- day intervals, then a modified radical mastec- tomy was performed. Patients with histologi cally confirmed complete remission and those with < 1 cm? of residual tumor received five additional cycles of VACP; those with no response to induction chemotherapy were crossed over fo receive five cycles of methotrex- ate, S-fluorouracil, and vinblastine (MFVb), Patients with partial response and = 1 em* or ‘more of residual tumor were randomly assigned to receive five additional cycles of either VACP or MEVb, All patients received radiation to the chest wall and regional lymph nodes. Eight patients whose tumors remained inoperable after induction chemotherapy underwent irradi- ation before mastectomy and MFVb. Irradiation had a minimal effect on wound healing provided ‘wound tension and thin skin flaps were avoided. If mastectomy resulted in a large defect, flap coverage consisting of healthy autogenous tis sue was preferred to the use of skin grafts Of 193 evaluable patients in this second trial (200 registered), 161 had a partial or greater clinical response to the three cycles of indue- tion chemotherapy. Among the patients with a partial response, no statistically significant dif- ference (p= .64) was detected in the 4-year sur- vival rates for the MFVb and VACP groups (75 and 58%, respectively) Of the 32 patients in this study whose tumors showed a minor or no response to the induction chemotherapy, only 16 remain alive and only 8 are disease-free at the time of writing. The lack of impact on sur vival of the crossover regimen in this study wa: probably due to the absence of an effective se Locally Advanced Breast Cancer 15S ond-line therapy. Significantly, there was exten- sive downstaging in a large proportion of patients in the study: 17 mastectomy specimen had no evidence of residual tumor, and 54 mas tectomy specimens had < 1 cm of residual tumor. This finding led us to consider the pos- sibility of performing breast conservation surgery for locally advanced disease. In a retrospective review of the mastectomy specimens in which the tumor shrank by = 50 percent with induction chemotherapy, the fac- tors most commonly associated with multiple- quadrant involvement that would exclude breast conservation surgery were demonstrated to be persistent skin edema, residual tumor size > 4 om, extensive intramammary lymphati invasion, and known mammographic evidence of multicentric disease® The objective in the third M. D. Anderson clinical trial (1989 to 1992) was to determine prospectively what fraction of patients with LABC may be candidates for breast conserva- tion surgery after induction chemotherapy? Of 203 evaluable patients with LABC who com- pleted four cycles of induction chemotherapy with (FAC), 51 (25 %) elected and underwent breast conservation surgery (Figure 10-1). The breast preservation rate for patients with ulcer- ative lesions or dermal lymphatic involvement (stage IIIB) was only 6 percent. With a median follow-up of > 60 months, only 5 (ten %) of the 51 patients who underwent breast conservation surgery had relapses in the breast. In the fourth M. D. Anderson clinical trial (1992 to 1996), the objective was to determine if high-dose chemotherapy would increase the extent of tumor downstaging with induction chemotherapy and allow more patients the option of breast conservation surgery. One hun- dred and seventy patients with LABC were ran- domly assigned to receive either four eycles of standard FAC (1000 mg/n® 5-fluorouracil, 50 mg/n? doxorubicin, and 500 mg/m? cyclophos phamide) at 21-day intervals or dose-intensive FAC (1200, 60, and 1000 mgin? of the three drugs, respectively) at 18-day intervals with