LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER

SPECIAL PROBLEMS IN BREAST CANCER THERAPY

0039-6109/96 $0.00

+ .20

LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER Kelly K. Hunt, MD, Frederick C. Ames, MD, S. Eva Singletary, MD, Aman U. Buzdar, MD, and Gabriel N. Hortobagyi, MD

BACKGROUND Despite recent advances in screening mammography and increased public awareness of the importance of early detection, locally advanced breast cancer is diagnosed in a significant number of women each year. It is estimated that 182,000 women in the United States were diagnosed with breast cancer in 1995 alone; and of these newly diagnosed tumors, 10% to 15% were already locoregionally advanced.55In underdeveloped countries, the rate of locally advanced disease at first diagnosis is estimated to be as high as 25% to 30%. The definition of a locally advanced breast tumor has changed over time as the staging system has evolved, but in general it includes patients with tumors larger than 5 cm (T3), tumors with skin or chest wall involvement (T4), or matted axillary nodal metastases (N2) (Table 1). In the past, many authors have lumped together large primary tumors or bulky nodal disease with inflammatory breast cancer. Current studies suggest, however, that inflammatory breast cancer differs in characteristics, growth pattern, treatment options, and prognosis from noninflammatory locally advanced breast cancer (LABC). Inflammatory breast cancer is discussed in the last article in this issue. The definition

From the Department of Surgical Oncology (KKH, FCA, SES) and the Department of Medical Breast Oncology (AUB, GNH), The University of Texas M. D. Anderson Cancer Center, Houston, Texas

SURGICAL CLINICS OF NORTH AMERICA

-

VOLUME 76 NUMBER 2 * APRIL 1996

393

394

HUNTetal

Table 1. TNM STAGING SYSTEM OF PRIMARY BREAST CANCER Primary Tumor (T) Tx Primary tumor cannot be assessed TO No evidence of primary tumor Tis Carcinoma in situ, intraductal carcinoma, lobular carcinoma in situ, or Paget's disease of the nipple with no associated tumor T1 Tumor 2 cm or less in greatest dimension T l a 0.5 cm or less in greatest dimension T1b More than 0.5 but not more than 1 cm in greatest dimension T l c More than 1 cm but not more than 2 cm in greatest dimension T2 Tumor more than 2 cm but not more than 5 cm in greatest dimension T3 Tumor more than 5 cm in greatest dimension T4 Tumor of any size with direct extension to chest wall or skin T4a Extension to chest wall T4b Edema (including peau d'orange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast T4c Both (T4a and T4b) T4d Inflammatory carcinoma Regional Lymph Node (N) Nx Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Metastasis to ipsilateral axillary lymph nodes N2 Metastasis to ipsilateral axillaty node(s) fixed to one another or other structures N3 Metastasis to ipsilateral internal mammary lymph node@) Distant Metastases (M) Mx Presence of distant metastasis cannot be assessed MO No distant metastasis M1 Distant metastasis (includes metastasis to supraclavicular lymph nodes)

of LABC has been narrowed somewhat by the most recent changes in staging, which eliminated ipsilateral supraclavicular nodal disease (Ml) and large primary tumors (Table 2) that show no clinical evidence of nodal involvement (T3NO)." Patients with ipsilateral supraclavicular nodal disease have been reclassified as having M1 or stage IV disease because this nodal basin is considered extraregional to the primary lymphatic drainage areas of the axilla and internal mammary basins. Patients with T3NO tumors, on the other hand, have been reclassified as having stage 1% disease because they have a more favorable prognosis, with a 5-year survival rate of 70% to 80%. The treatment of LABC has also evolved from primarily local modalities to treatment regimens that combine systemic and local therapy. The realization that patients with LABC are likely to have undetectable micrometastases at diagnosis has led to systemic treatment assuming the major focus of the multimodality approach. We will discuss the controversies surrounding the treatment of LABC, including the sequence of local and systemic treatments and the role of breast-conserving surgery after tumor downstaging with systemic therapy. NATURAL HISTORY

Haagensen and Stoutz5were the first to carefully examine the results of radical mastectomy in the treatment of 74 patients with LABC. They

LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER

395

Table 2. AMERICAN JOINT COMMITTEE FOR CANCER STAGE GROUPING IN PRIMARY BREAST CANCER Stage Grouping Stage 0 Stage I Stage HA Stage IIB Stage IllA

Stage IllB Stage IV

Tis T1 TO T1 T2 T2 T3 TO T1 T2 T3 T4 Any T Any T

NO NO N1 N1 NO N1 NO N2 N2 N2 N1, N2 Any N N3 Any N

MO MO MO MO MO MO MO MO MO MO MO MO MO M1

categorized “inoperable breast cancer” in any patient with (1)extensive edema of the skin over the breast, (2) satellite nodules in the skin over the breast, (3) intercostal or parasternal nodules, (4) edema of the arm, (5) proven supraclavicular metastases, or (6) inflammatory type of carcinoma. The local recurrence rate in these patients ranged from 14.3% to as high as 66.7% in those with arm edema. An even more striking finding in this group was that only two patients were alive and diseasefree at 5 years and that both of these patients experienced recurrence 1 year later. Even though this was a heterogeneous group of patients, the futility of radical mastectomy both for cure and for local tumor control was evident. Haagensen and Stoutz5also described five ”grave clinical signs” that were indicators of a poor prognosis but were not specific contraindications to radical mastectomy. These included ulceration, edema of limited extent, fixation of the tumor to the chest wall, axillary lymph nodes 2.5 cm or larger shown to contain metastases, and fixed axillary nodes that contained metastases. In this group of 35 patients, the local recurrence rate was 45.7% at 5 years, with only two patients free of disease at 5 years. Other clinical signs of locally advanced disease included a single tumor larger than 10 cm in size, multiple tumors in one breast, redness of the skin, and skin involvement. The development of distant metastases was common in these patients; their 5-year diseasefree survival ranged from 11%to 44%. From these series, it was concluded that clinical criteria should be used in judging the operability of patients with LABC because radical mastectomy was not curative, and both local and distant metastatic disease recurred in the majority of patients. The need for treatment modalities in addition to surgery was evident.

396

HUNTetal

LOCAL THERAPEUTIC MODALITIES

Surgery Alone For many years, the Halsted radical mastectomy was the standard treatment for breast cancer. Table 3 summarizes the results of surgery alone in the treatment of LABC; these studies were retrospective and did not follow uniform staging classifications. Some included stage I1 patients in addition to LABC, and some patients were treated with radiation therapy and chemotherapy. Patients with more advanced disease experienced both local and distant failures despite the radical procedure. The variation in 5-year survival rates from 5.7% to 53% in these series could be due to the heterogeneous nature of the patients 24, ~ 548 , who were grouped together by. their LABC diagn~sis.~, A review by Fracchia et alZ4at Memorial-Sloan Kettering Cancer Center examined the experience with stage I11 breast cancer patients from 1965 to 1975. Involvement of axillary lymph nodes was the most significant factor determining recurrence and survival. Patients with negative lymph nodes had a 10-year survival rate of 753'0, whereas the 10-year survival rate was 21% in those with positive lymph nodes. The presence of Haagensen's grave signs did not seem to influence prognosis if the lymph nodes were negative. Interestingly, the local recurrence rate at 5 years was only 25% in the node-positive patients, which is significantly lower than that reported in other series?, 25 The Fracchia group compared the use of surgery alone to radiation alone and found local recurrence higher in the radiation-alone group. This may be due to the fact that patients treated with surgery alone were in a better prognostic group than those treated with radiation alone; the latter may not have been acceptable surgical candidates. These studies confirmed that surgery alone was inadequate treatment in the management of patients with LABC. Furthermore, the wide Table 3. SURGERY ALONE IN TREATMENT OF LOCALLY ADVANCED BREASTCANCER

Author

Institution

Haagensen and Columbia-Presbyterian Stout25 Schottenfeld et a148 Memorial Sloan-Kettering Cancer Center Arnold and Mount Sinai Hospital Lesnick5 Fracchia et aIz4 Memorial Sloan-Kettering Cancer Center

5-Year Local Recurrence No. of Rate Patients (%)

5-Year Survival

10-Year Disease-Free Survival

("/I

(W

45.7

62

6 '

53

29t

50

50

33

22

207

2%

43

27.1

*Includes stage II and Ill patients tl0-year survival. Thirty patients were treated with postoperative radiation $Node-positive only

5.7

-

35

LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER

397

variation in results demonstrated the patient’s heterogeneity rather than any true treatment effect. Even with aggressive surgical techniques, patients with advanced local disease had a high incidence of localregional recurrence. Most important, surgery did not change the pattern of distant failure in patients who probably had micrometastatic disease at the time of diagnosis. Radiation Alone

The use of radiation therapy alone in the treatment of locally advanced noninflammatory breast cancer was no more effective than surgery alone (Table 4). The local recurrence rates of 36% to 72% were even higher than those reported for surgery alone. The radiation therapy studies were difficult to compare with surgical series because many patients in the radiation-alone series had more advanced disease and were inoperable. Zucali and associatess6at the National Tumor Institute in Milan selected 133 of 454 patients to undergo radical mastectomy 6 to 8 weeks after completing radiation. It was not surprising that this subset of patients had a median survival of 3.9 years, compared with 2.1 years for the radiation-alone group. The selection was not random; usually patients who achieved a complete clinical remission were selected for surgical therapy. The investigators also compared kilovoltage to cobalt radiation therapy but found no difference in results. Rubens and colleaguesMof Guy’s Hospital in London reviewed 184 patients with inoperable stage I11 breast cancer who were treated with radiation therapy alone (Table 4). The local recurrence rate of 72% was quite high, but again, they had selected patients with advanced disease who were not operable. The heterogeneous nature of patients defined Table 4. RADIATION ALONE IN THE TREATMENT OF LOCALLY ADVANCED BREASTCANCER ~~

~

Author Zucali et a156

Year

Institution

1976 lnstituto Nazionale Tumori Rubens et a144 1977 Guy’s Hospital Bruckman et all3 1979 Joint Center for Radiation Therapy Rao et a143 1982 Mallinckrodt Institute of Radiology Harris et a P 1983 Joint Center for Radiation Therapy

5-Year Local Recurrence No. of Rate (%) Patients

5-Year Disease-Free Survival

(“/.I

321

49’

21

184 116$

72 36t

18 22

54

51

16-20

137

46

28

*Local recurrence at 2 years. tSome patients treated with excisional biopsy and/or interstitial implant. $41 patients received some adjuvant therapy.

398

et a1

as LABC in those early studies made comparisons among treatment groups difficult. Rao and at the Mallinckrodt Institute showed that the size of the primary tumor significantly influenced the rate of local failure, which was 44% for tumors 0 to 8 cm in size versus 76% for tumors larger than 8 cm in size. Five-year disease-free survival was also better in the group with smaller tumors. Likewise, advanced nodal disease was associated with a higher regional failure rate. This difference in local-regional failures was no longer evident when patients were treated with a combination of radiation therapy and surgery, which suggested that the two treatment modalities might provide better results if used together. The patients’ high rate of distant relapse, however, emphasized the need for systemic therapy as well. Bruckman and Harris and their associates reported series from the Joint Center for Radiation Therapy in treating patients for LABC.13,26 Bruckman et a1 evaluated 116 consecutively diagnosed patients whose local control rate was 64% at 5 years. The outcome for these patients was more favorable because one third had tumors without skin or chest wall involvement and nearly one third were node-negative. Forty-one .of the patients received some form of adjuvant therapy, which may explain their higher disease-free survival rate of 28%. Both the Bruckman and Harris groups showed that doses of more than 6000 rad were associated with improved local tumor control. A retrospective review of patients treated by radiation therapy alone at the Princess Margaret Hospital and the Gustave-Roussy Institute confirmed that higher radiation doses could decrease twofold the relative risk of local-regional failure.6 However, the incidence of disabling complications (arm edema, impaired shoulder mobility, rib fractures, brachial plexopathy) increased with the increased dose of radiation. In summary, the use of radiation therapy alone in treatment of LABC resulted in local failure rates higher than those in patients treated with surgery alone. These results were due in large part to the fact that patients selected for treatment with radiation alone were usually inoperable. Combined Surgery and Radiation Therapy

In early attempts to improve local-regional control in treating patients for LABC, radiation therapy was combined with surgical therapy.7, *, 54, 56 Although these studies showed promising results in localregional control, they failed to address the systemic nature of LABC, and patients still died of metastatic disease. The lessons learned in those years emphasized the need for additional treatment modalities. First, even though combined radiation and surgical therapy delayed the time to first local-regional relapse, there was no significant survival advantage. Second, preoperative radiation therapy was often able to convert an inoperable breast cancer to an operable one. Third, preoperative

399

LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER

radiation therapy did not seem to differ from postoperative radiation in providing additional local-regional control. Last, a combination of surgery and radiation therapy provided the maximum chance for localregional control over high-dose radiation therapy or surgery alone. Table 5 summarizes selected series in which combination surgery and radiation therapy were used pre- or postoperatively to treat LABC patients. The results showed that even combining radiation therapy and surgery did not eliminate local-regional failures. MULTIMODAL THERAPY

Haagensen and Stout'sz5early paper on the criteria of operability in carcinoma of the breast made clear that the vast majority of patients with locally advanced disease would develop distant metastatic disease. This has been confirmed in multiple trials of surgery and radiation therapy alone or in combination. Early work with multimodality therapy of breast cancer included surgical and radiation-induced oophorectomy. Single-agent chemotherapy trials showed an improvement in overall and disease-free survival, but the small numbers of patients they included were insufficient for reaching significant conclusions. Multimodality therapy that included surgery, radiation therapy, chemotherapy, and hormonal therapy has had the greatest impact on survival. Many authors have reported improved survival and freedom from distant relapse in patients who received adjuvant chemotherapy after local treatment with surgery or radiation therapy.lO,13, 24, 26* 32, 38 Bitran and colleagues9 treated 34 patients who had stage I11 and IV breast cancer

Table 5. COMBINATION SURGERY AND RADIATION THERAPY IN TREATMENT OF LOCALLY ADVANCED BREAST CANCER

Author Preoperative Radiation Cadeq5 Zucali et alse Whitaker and Battersby% Arnold and Lesnick5 Townsend et a152 Postoperative Radiation Arnold and Lesnick5 Bedwinek et ale Montague and Fletcher35

Year 1949 1976 1977 1979 1984 1979 1982 1985

Institution

No. of Patients

Westminster Hospital lnstituto Nazionale Princess Alexandra Hospital Mount Sinai Hospital University of Texas

95 133 68

Mount Sinai Hospital Mallinckrodt Institute of Radiology M. D. Anderson Cancer Center

'Includes distant relapses. t 1 7 patients had preoperative radiation $10-year disease-free survival.

Local Recurrence Rate (%)

-

5-Year Survival (%) 10 45

77.9 70' 11

32 10-35

122 931

70' 12-13

30

132

13

43.3*

54 53

-

400

et a1

with radical mastectomy, followed by postoperative radiation therapy, then 12 months of chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). All 34 women completed the course of treatment, but all developed pulmonary fibrosis. This degree of toxicity was unusual, but it discouraged many physicians from using multimodal therapies. The reported median relapse-free survival in the Bitran group’s study was 24 months. Notably, they observed a much higher 5year survival in premenopausal (74%) than postmenopausal patients (119’0). Estrogen receptor status did not, however, predict survival. Neoadjuvant Therapy

The use of neoadjuvant or induction chemotherapy was first reported in the 1970s. Induction therapy was used initially to convert unresectable tumors to smaller tumors more amenable to local control with either surgery or radiation therapy. An added advantage of this approach was the ability to assess the patient’s response to treatment both clinically after a defined number of courses of chemotherapy and pathologically after surgical resection. Table 6 contains an overview of selected neoadjuvant trials. Perez and c011eagues~~ reported their results of a pilot study by the Southeastern Cancer Study Group in 1979. This small study included 14 patients (five patients had inflammatory breast cancer and five had recurrences after mastectomy). All patients were treated with 5-flUOrOuracil, Adriamycin (doxorubicin),and cyclophosphamide (FAC) for two courses, followed by local therapy or radiation concurrently with cyclophosphamide and 5-fluorouracil (CF). In the Perez group’s study, all patients received an additional eight courses of FAC. All but three of the patients had complete regression of their tumors following radiation therapy. The primary tumor showed partial regression (50% to 75%) in 65% of the patients after the first two courses of FAC. In a similar study by Rubens and associates45at Guy’s Hospital, the investigators examined the feasibility of radiation therapy and chemotherapy as the primary management of LABC. Patients were assigned to either induction chemotherapy for four cycles followed by radiation therapy, or to radiation therapy followed by four cycles of doxorubicin and vincristine (AV). Both groups received maintenance chemotherapy of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). The objective response rate was high in both groups (83% and 92%), but the local relapse rate was also high (500/, and 58%). The Rubens group compared these patients’ median duration of response with that of a similar group of patients previously treated with radiation therapy alone and found a statistically significant longer duration of response (33 months versus 10.5 months) in the more recent patients but no statistically significant difference in survival. Clearly, induction chemotherapy was feasible but did not show a significant survival benefit in this 1980 study.

lnstitut Jules Bordet University Hospital Tours, France Thomas Jefferson University Hospital M. D. Anderson Cancer Center

1983

1988 1993

1994

1995

Valagussa et als3

Piccart et al” Calais et aP6

Schwartz et alas

Buzdar et all4

=

lnstituto Nazionale Tumori

1982

Aisner et a13

P

University of Malyland

1980

Rubens et alas

Institution

1979

Perez et aP7

189

or CMFx3-2A (if no response)>S>CMF FACx3->S->CTXx2 yrs FACx3->XRT->CTXx2 yrs FACx3->S+ XRT-XTXx2 yrs or VACPx3->S->VACP

=

84 200

hormonal therapy; M

88

85

68 51

174

46 59

65 95

CMFx3->S->CMF

92 74

12 27t

79.6

83

12

(“A) 80

14*

80

+

+ HT

+ CF->FACx8

Treatment

AVx4->XRT->CMFx8 or XRT->AVx4->CMFx8 FACx3->S->CTXx2 yrs or FAC V P-S>CTX AVx3-4->S->AV AVX~-~->XRT->AV or AVx3-4->XRT CTX+ XRT+ HT->S->CTX MitVdCFxd->S XRT->HT

+ +

FACx2->XRT

+

Complete Partial Response Rate

A = Adriamycin (doxorubicin HCI); C = cyclophosphamide; CR = complete response; CTX = chemotherapy; F = 5-fluorouracil; HT prednisone; S = surgery; V = vincristine; Vd = vindesin; XRT = radiation therapy. ‘Includes 5 patients with inflammatory breast cancer (IBC) and 4 patients with chest wall recurrence after mastectomy. tlncludes patients with IBC and metastatic disease. *Survival in patients responding to chemotherapy. §Stage IllA survival at 15 years, 54%; stage Ill6 survival at 15 years, 24%.

Southeastern Cancer Study Group Guy’s Hospital

Year

Author

Number of Patients

Table 6. SELECTED NEOADJUVANT TRIALS OF TREATMENT OF LOCALLY ADVANCED BREAST CANCER

=

methotrexate; Mit

Median Survival (Months)

=

mitoxantrone;

54(111A)§ 24( IIIB)§

6%

73

-

19.7

49.4 35.7

-

-

-

5-Year Overall Survival (%)

402

et a1

Two studies from Italy showed that maintenance chemotherapy after local therapy was important to freedom from progression and improved overall survival. DeLena and colleagueszofrom the National Tumor Institute in Milan reported their results of a prospective, randomized trial of multimodal therapy for LABC in 1981. They compared local therapies of mastectomy or radiation therapy after induction therapy with AV for three cycles. After local-regional therapy, all patients received an additional seven cycles of chemotherapy (AV). The total response rate at the end of treatment was the same in the surgery and radiation therapy groups (75%), and there was no significant difference in patterns of failure or survival. Valagussa et a153 reported another study from Milan in 1983 with three groups of patients, finding the local-regional failure rate much,higher in patients treated with radiation, even when maintenance chemotherapy was administered. These results led them to conclude that cytoreductive surgery should be done whenever feasible before maintenance chemotherapy is begun. Because a number of patients with LABC were technically inoperable at presentation, however, surgery prior to chemotherapy would not be a reasonable approach for all patients. . University of Texas M. D. Anderson Cancer Center researchers were among the first to support the use of all three modalities (surgery, chemotherapy, and radiation therapy) in the treatment of LABC.28An initial report included results of 52 patients treated with three cycles of FAC and immunotherapy with bacille Calmette-GuQin (BCG), followed by local therapy and adjuvant chemotherapy to complete 2 years of treatment. After local therapy, 94% of patients were rendered free of disease. The local recurrence rate was 21%, and distant metastases developed in 40% of patients. Although treatment was well tolerated, only 14 of the 52 patients completed 2 years of treatment. The median diseasefree survival was only 11 months for patients who did not complete 2 years of therapy. The investigators then compared this group with a historical control group of 52 patients treated by simple mastectomy and postoperative radiation therapy.29Although the local recurrence rate was similar in the two groups, median disease-free survival was statistically better in the FAC treated group, especially in patients who had supraclavicular nodal disease. Kantajian et a1,3O also from the M. D. Anderson Cancer Center, followed this initial report with a series of 93 patients with LABC who were treated with the same regimen. The complete and partial response rate to chemotherapy was 86%, which allowed 89 patients to be rendered free of disease after local therapy. The estimated median length of survival was 66 months. Age, menopausal status, and the presence of supraclavicular lymphadenopathy had no effect on prognosis. Multimodal Programs with Hormonal Therapy

Because adjuvant therapy in the form of cytotoxic chemotherapy or hormonal therapy alone was shown to reduce the risk of relapse and

LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER

403

mortality in patients with breast cancer, many investigators believed that a combination of chemotherapy and hormonal therapy would produce an even greater benefit. Loprinzi and from the University of Wisconsin-Madison were among the first to report the use of a combined program of surgery with radiation and systemic chemohormonal therapy. They treated 32 women with surgery followed by two courses of chemohormonal therapy of CMF with prednisone (P) and tamoxifen (T) (CMFPT).Patients then underwent local-regional radiation therapy, followed by maintenance chemohormonal therapy with CMFPT, alternating with doxorubicin, vincristine, and tamoxifen. The median disease-free survival was reported as 29.5 months, with an actuarial 3-year survival of 65%. The incidence of cardiotoxicity (24%) appeared to be greatest in patients receiving left-sided chest wall irradiation. In this small group of patients, women whose gross disease was not resected had a significantly shorter disease-free survival. Lippman and colleagues31 at the National Cancer Institute used induction chemotherapy with hormonal synchronization, followed by radiation therapy with or without debulking surgery, in 51 patients with LABC. Patients received induction chemotherapy until they attained a maximum objective clinical response before local therapy was considered. Patients who achieved a complete response (CR) went on to radiation therapy, whereas those who had a partial response or stable disease underwent debulking surgery prior to radiation therapy. All patients had 6 additional months of chemotherapy after local therapy. Their systemic regimen included cyclophosphamide and Adriamycin on day 1, tamoxifen on days 2 to 6, Premarin every 12 hours for three doses on day 7, and methotrexate followed by 5-fluorouracil and leucovorin rescue on day 8. The patients’ overall response to chemotherapy was go%, but only 52% of patients were complete responders. Seventy-one percent of the patients with a clinical CR were confirmed to have a pathologic CR after multiple biopsies or mastectomy (20 and 2 patients, respectively). These results were reported before median survival or median time to disease progression had been reached; however, 12 of 50 evaluable patients had relapsed at the time of their report. In an update of this study, Swain and associates51used neoadjuvant chemotherapy and hormonal synchronization in a total of 76 patients who also were treated until they reached the maximum objective response before any local therapy began. Median time to disease progression was 35.9 months for stage IIIA (T3NO) and 34.2 months for stage IIIB patients. Twenty-three patients were considered to have a histologic CR after biopsy, and nine of these patients experienced local-regional relapses. Morrow et a136 evaluated the response of patients to induction chemohormonal therapy with two cycles of FAC and tamoxifen, followed by modified radical mastectomy and postoperative chemotherapy alternating with chest wall radiation therapy. No patients experienced a CR, but in 77% of patients tumor size was reduced by more than 50% after induction therapy.

404

HUNT et a1

A prospective, randomized study that showed no improvement in overall response rate or freedom from progression or recurrence when tamoxifen was added to preoperative and postoperative chemotherapy was reported by Cocconi et a1.18 The study included 49 patients who had four courses of CMF both before and after surgery. Not only was there no improvement in the tamoxifen-treated group, but they tended to have a shorter overall survival compared with the patients receiving CMF alone. Thus, according to these reports, estrogenic recruitment and the addition of hormonal therapy to standard chemotherapy regimens did not achieve improved survival or freedom from local-regional relapse over other neoadjuvant regimens. The findings of higher pathologic CR rates may be the result, in part, of the evaluation of most patients with multiple needle biopsies, not total mastectomy that would allow the entire breast to be examined pathologically. The concept of treatment to maximum CR before local therapy may provide more flexibility to the surgical treatment of patients with advanced disease. Lippman and associates reported that a median number of five chemotherapy cycles was needed to achieve a CR. ’ Alternate treatment approaches, including dose-intensification chemotherapy regimens with or without bone marrow transplant, are currently under investigation. To date, no significant survival advantage has been demonstrated in patients with LABC. Breast Conservation in the Setting of Multimodal Therapy

The concept of breast conservation in patients with LABC was initially practiced to spare patients surgery who already had an extremely poor prognosis. Initial studies with radiation therapy alone accomplished breast conservation, but at the expense of a high rate of local-regional failure and distant relapse. Even studies of multimodal therapy in which only radiation was used as local therapy have had local-regional failure rates as high as 30% to 50%. The ability to reduce local failures by combining surgery and radiation therapy makes breast conservation treatment more appealing. Because induction chemotherapy may result in significant reductions in the size of the primary tumor, many patients with LABC would be candidates for breast conservation with a combination of surgery and radiation therapy. In 1990, Bonadonna et al” first reported the use of induction chemotherapy to downstage primary tumors and allow subsequent breastsaving surgery. The criterion for breast-saving surgery was a reduction in the tumor size to less than 3 cm. The group was able to avoid mastectomy for 127 (81%)of the 157 patients who had a surgical procedure. The treatment regimen consisted of three to four cycles of chemotherapy (CMF, FAC, or FEC [5-fluorouracil, epirubicin, cyclophosphamide]), followed by surgery and postoperative radiation therapy. Only

LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER

405

116 women received postoperative adjuvant chemotherapy. Complete responses were seen after chemotherapy in 27 women, although histopathologic CR occurred in only nine. Up to 60% of the patients had at least a partial response to the induction chemotherapy. Among the first 83 patients who underwent surgery with at least 12 months of followup, the disease recurred in 13. Only one of the 75 women treated with breast conservation surgery experienced a local recurrence during this period. One patient treated with mastectomy had a local recurrence, and the remaining 11 patients developed distant metastases. The M. D. Anderson Cancer Center experience with induction chemotherapy also noted excellent response rates, with a complete response rate of 16.7% and a partial response rate of 70.7% after three cycles of FAC chem~therapy.~~ This information led Singletary and associates50to investigate the feasibility of breast-conserving surgery following induction chemotherapy. An evaluation of 143 patients treated with induction chemotherapy followed by mastectomy with axillary lymph node dissection revealed that 33 (23%)patients would have been appropriate candidates for breast conservation based on criteria of tumor size less than 5 cm, resolution of skin edema, and absence of multicentric tumors or extensive intramammary lymphatic invasion. Of the 33 patients who had a significant reduction in tumor size, 42% had no residual tumor in the mastectomy specimen and 45% had negative nodes. Booser et all2 reported recent results of breast-conserving surgery after multimodal therapy at the M. D. Anderson Cancer Center. The study included 207 women who received induction chemotherapy with FAC, followed by surgery, postoperative adjuvant chemotherapy, and radiation therapy. Forty patients were treated with segmental resection and axillary dissection, whereas some others were candidates for breast preservation but preferred mastectomy over the conservative approach. Two other studies of the results of breast-conserving treatment after induction chemotherapy included both stage I1 and I11 patients.l6*49 Calais et all6 found that breast preservation was possible in 34 of 80 patients (42.5%) after three courses of induction chemotherapy with mitoxantrone, vindesin, cyclophosphamide, and 5-fluorouracil. Candidates for breast conservation underwent either tumorectomy and radiation or radiation therapy alone with brachytherapy. There were two local recurrences in the conservation group and three in the mastectomy group; 20 patients developed distant metastases. Table 7 summarizes the results of breast preservation in the treatment of LABC. The initial findings for breast-conserving surgery and radiation therapy in patients responding to induction chemotherapy have been promising. Figure 1 illustrates the postoperative result in a patient who presented with locally advanced breast cancer to the M. D. Anderson Cancer Center in 1991. She was not a candidate for breastconserving surgery at presentation because of the size of the primary tumor. She was treated with four cycles of induction chemotherapy with FAC. She then had segmental mastectomy with axillary node dissection.

406

HUNT et a1

Table 7. BREAST CONSERVATION AFTER MULTIMODALITY TREATMENT IN LOCALLY ADVANCED BREAST CANCER

Author

Year

Institution

Bonadonna et all1 1990 lnstituto Nazionale Tumori Booser et all2 1992 M. D. Anderson Cancer Center Calais et alle 1993 University Hospital, Tours, France Scholl et aI4' 1994 lnstitut Curie, Paris, France Schwartz et 1994 Thomas Jefferson University

No. of Patients

Breast Conservation Rate

(%I

5-Year Survival

165*

81

("/.I -

146t

27

-

80*

42.5

73

390s

79.7

78-86

189

36

61ll

"Includes patients with stage II disease. tSome patients refused breast conservation treatment. *Includes some patients with stage II disease. §Patients had surgery if they had persistent tumor after radiation therapy. (Five-year survival rate for patients having a response to chemotherapy.

She received adjuvant chemotherapy postoperatively, followed by breast irradiation. She remains disease free 4 years postoperatively. Although most of the reports on breast-conserving treatment after induction chemotherapy lacked extended follow-up, local-regional re-

Figure 1. Results after breast-conserving treatment in a 49-year-old woman with locally advanced breast cancer. The patient was not a candidate for breast conservation on presentation. Following tumor downstaging with induction chemotherapy, the patient underwent a segmental mastectomy and an axillary dissection. She had postoperative adjuvant chemotherapy followed by radiation therapy.

LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER

407

lapse did not seem to be more prevalent in the patients treated with breast preservation methods. The rate of development of distant metastatic disease was comparable to that of studies in which all patients were treated with mastectomy, which underscores the need for still more effective systemic therapies. PROGNOSTIC FACTORS

Tumor size and involvement of axillary lymph nodes have been shown to predict prognosis in patients with breast cancer.23When the influence of preoperative chemotherapy on the prognostic significance of lymph node metastases was examined by McCready and c011eagues~~ at the M. D. Anderson Cancer Center, they determined by multivariate analysis that the number of metastatic lymph nodes had more prognostic value than such other factors as tumor stage at presentation, clinical and pathologic response rate to treatment, and menopausal status. The number of positive lymph nodes after chemotherapy reflected response to treatment, independent of the clinical response of the primary tumor. In the McCready study, 5-year survival in patients with no positive nodes was 70%, for those with one to three metastatic nodes it was 62%, for patients with 4 to 10 positive nodes it was 47%, and for patients with more than 10 positive nodes it was 21%. The study suggested that surgical staging of the axilla is still important after induction chemotherapy. Assessment of histopathologic response to induction chemotherapy was examined by several investigators, who questioned its influence on survival.17, Feldman et alZ1reviewed pathologic specimens from 90 patients treated with induction chemotherapy and mastectomy at the M. D. Anderson Cancer Center to assess the degree of tumor reduction. Fifteen patients showed no macroscopic tumor on gross examination, and six patients were without microscopic residual tumor. These patients experienced a longer disease-free survival than did the other 75 patients whose response to induction therapy was lower. Clinical response to chemotherapy was not as accurate in determining outcome. Patients who had no macroscopic disease at pathologic evaluation had a 93% overall 5-year survival rate. Again, this information obtained from surgery may be important in the treatment plan for patients with LABC who have completed induction chemotherapy and local therapy. SUMMARY

Treatment of locally advanced noninflammatory breast cancer has changed markedly over the past 50 years. Haagensen’s description of the clinical signs that define inoperable and operable tumors was the first realization that radical surgery alone could not cure the majority of women with locally advanced disease. Studies of the use of local therapy

alone (surgery or radiation therapy) confirmed that most patients developed both distant metastatic disease and a high rate of local-regional failure. Combination surgery and radiation therapy regimens improved local control but did not influence long-term survival. The advent of successful multimodal regimens incorporating systemic treatment (chemotherapy or chemohormonal therapy) as well as local therapy (surgery and radiation) has significantly improved disease-free and overall survival as well as local-regional control.40 The benefits of neoadjuvant and adjuvant chemotherapy regimens have been debated.', 2, 22, 41, 42 Neoadjuvant therapy allows clinical and pathologic assessment of tumor response to the chemotherapy regimen. In addition, local-regional control seems to be improved, and reductions in the size of the primary tumor allow breast-preserving procedures, even in patients initially not believed to be candidates for resection. Longer follow-up of these conservatively treated patients will be needed, however, to determine whether local-regional control is preserved. References 1. Abeloff M, Beveridge R, Donehower R, et al: Sixteen-week dose-intense chemotherapy in the adjuvant treatment of breast cancer. J Natl Cancer Inst 82:570, 1990 2. Ahem V, Barraclough B, Bosch C, et a1 Locally advanced breast cancer: Defining an optimum treatment regimen. Int J Radiat Oncol Biol Phys 28867, 1994 3. Aisner J, Morris D, Elias E, et al: Mastectomy as an adjuvant to chemotherapy for locally advanced or metastatic breast cancer. Arch Surg 117882, 1982 4. American Joint Committee on Cancer: Manual for Staging of Cancer, ed 4. Philadelphia, JB Lippincott, 1992, p 149 5. Amold D, Lesnick G: Survival following mastectomy for stage I11 breast cancer. Am J Surg 137362, 1979 6. Arriagada R, Mouriesse H, Rezvani A, et al: Radiotherapy alone in breast cancer: Analysis of tumor and lymph node radiation doses and treatment-related complications: The experience of the Gustave-Roussy Institute and The Princess Margaret Hospital. Radiother Oncol 271, 1993 7. Balawajder I, Antich P, Boland J: An analysis of the role of radiotherapy alone and in combination with chemotherapy and surgery in the management of advanced breast carcinoma. Cancer 51:574, 1983 8. Bedwinek J, Rao V, Perez C, et a1 Stage III and localized stage IV breast cancer: Irradiation alone vs irradiation plus surgery. Int J Radiat Oncol Biol Phys 831, 1982 9. Bitran J, Desser R, Schifeling D, et a1 Multimodality therapy of stage I11 adenocarcinoma of the breast. J Surg Oncol225, 1983 10. Bonadonna G, Valagussa P, Zambetti M, et al: Locally advanced breast cancer: 10-year results after combined treatment. Proceed Am SOCClin Oncol 79, 1988 11. Bonadonna G, Veronesi U, Brambilla C, et al: Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. J Natl Cancer Inst 821539, 1990 12. Booser D, Frye D, Singletary S, et al: Response to induction chemotherapy for breast cancer: A prospective multimodality treatment program. Proceed Am SOCClin Oncol 11:82, 1992 13. Bruckman J, Harris J, Levene M, et a1 Result of treating stage 111 carcinoma of the breast by primary radiation therapy. Cancer 43985, 1979 14. Buzdar A, Singletary S, Booser, D, et a1 Combined modality treatment of stage I11 and inflammatory breast cancer-M.D. Anderson Cancer Center experience. Surg Oncol Clin North Am 4715, 1995

LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER

409

15. Cade S Treatment and results in cancer of the breast. Am J Roentgen01 62:326, 1949 16. Calais G, Descamps P, Chapet S, et al: Primary chemotherapy and radiosurgical breastconserving treatment for patients with locally advanced operable breast cancers. Int J Radiat Oncol Biol Phys 2637, 1993 17. Cocconi G, Di Blasio B, Alberti G, et al: Problems in evaluating response of primary breast cancer to systemic therapy. Breast Cancer Res Treat 4309, 1984 18. Cocconi G, Di Blasio B, Bisagni G, et al: Neoadjuvant chemotherapy or chemotherapy and endocrine therapy in locally advanced breast carcinoma: A prospective, randomized study. Am J Clin Oncol 13226, 1990 19. Cocconi G, De Lisi V, Boni C, et al: Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer: A prospective randomized study. Cancer 51:581, 1983 20. De Lena M, Varini M, Zucali R, et al: Multimodal treatment for locally advanced breast cancer. Cancer Clin Trials 4:229, 1981 21. Feldman L, Hortobagyi G, Buzdar A, et al: Pathologic assessment of response to induction chemotherapy in breast cancer. Cancer Res 46:2578, 1986 22. Fisher B, Rockette H, Robidoux A, et a1 Effect of preoperative therapy for breast cancer (BC) on local-regional disease: First report of NSABP B - 18. Proceed Am SOC Clin Oncol 1364, 1994 23. Fisher B, Slack N, Bross I, et al: Cancer of the breast: Size of neoplasm and prognosis. Cancer 24:1071, 1969 24. Fracchia A, Evans J, Eisenberg B: Stage 111 carcinoma of the breast: A detailed analysis. Ann Surg 192:705, 1980 25. HaaEensen C, Stout A: Carcinoma of the breast. 11. Criteria of operability. Ann Surg 118:g59, 1943 26. Harris I, Sawicka 1, Gelman R, et al: Management of locallv advanced carcinoma of the breast by primary radiation therapy. I n t j Radiat Oncol Biol Phys 9:345, 1983 27. Hortobagyi G, Ames F, Buzdar A, et al: Management of stage I11 primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 62:2507, 1988 28. Hortobagyi G, Blumenschein G, Spanos W, et al: Multimodal treatment of locoregionally advanced breast cancer. Cancer 51:763, 1983 29. Hortobagyi G, Spanos W, Montague E, et al: Treatment of locoregionally advanced breast cancer with surgery, radiotherapy, and combination chemoimmunotherapy. Int J Radiat Oncol Biol Phys 9:643, 1983 30. Kantarjian H, Hortobagyi G, Smith TL, et al: The management of locally advanced breast cancer: A combined modality approach. Eur J Cancer Clin Oncol20:1353, 1984 31. Lippman M, Sorace R, Bagley C, et al: Treatment of locally advanced breast cancer using primary induction chemotherapy with hormonal synchronization followed by radiation therapy with or without debulkmg surgery. Natl Cancer Inst Monog 1:153, 1986 32. Lopez M, Andriole D, Kraybill W, et al: Multimodal therapy in locally advanced breast carcinoma. Am J Surg 160:669, 1990 33. Loprinzi C, Carbone ,’l Tormey D, et al: Aggressive combined therapy for advanced local-regional breast carcinoma. J Clin Oncol 2:157, 1984 34. McCready D, Hortobagyi G, Kau S, et al: The prognostic significance of lymph node metastases after preoperative chemotherapy for locally advanced breast cancer. Arch Surg 124:21, 1989 35. Montague E, Fletcher G: Local regional effectiveness of surgery and radiation therapy in the treatment of breast cancer. Cancer 55:2266, 1985 36. Morrow M, Braverman A, Thelmo W, et a1 Multimodal therapy for locally advanced breast cancer. Arch Surg 121:1291,1986 37. Perez C, Presant C, Philpott G, et al: Phase 1-11 study of concurrent irradiation and multi-drug chemotherapy in advanced carcinoma of the breast: A pilot study by the southeastern Cancer Study Group. Int J Radiat Oncol Biol Phys 5:1329, 1979 38. Perloff M, Lesnick G, Korzun A, et a1 Combination chemotherapy with mastectomy or radiotherapy for stage 111breast carcinoma: A Cancer and Leukemia Group B study. J Clin Oncol 6261, 1988

410

et a1

39. Piccart M, De Valeriola D, Paridaens R, et al: Six-year results of a multimodality treatment strategy for locally advanced breast cancer. Cancer 622501, 1988 40. Pierce L, Lippman M, Ben-Baruch N, et al: The effect of systemic therapy on localregional control in locally advanced breast cancer. Int J Radiat Oncol Biol Phys 23:949, 1992 41. Powles T, Hickish T, Makris A, et al: Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 13547, 1995 42. Ragaz J, Knowling M, Jones G, et al: Comparability of preoperative (neoadjuvant) (pre) and postoperative (post) (TH) for locally advanced breast cancer (LABC). Proceed Am Assoc Cancer Res 28:197,1987 43. Rao D, Bedwinek J, Perez C, et al: Prognostic indicators in stage I11 and localized stage IV breast cancer. Cancer 50:2037, 1982 44. Rubens R, Armitage P, Winter P, et al: Prognosis in inoperable stage 111 carcinoma of the breast. Eur J Cancer 13805,1977 45. Rubens R, Sexton S, Tong D, et al: Combined chemotherapy and radiotherapy for locally advanced breast cancer. Eur J Cancer 16:351, 1980 46. Sataloff D, Mason 8,Prestipino A, et al: Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: A determinant of outcome. J Am Coll Surg 180:297,1995 47. Scholl S, Fourquet A, Asselain B, et al: Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: Preliminary results of a randomised trial: S6. Eur J Cancer 30:645, 1994 48. Schottenfeld D, Nash A, Robbins G, et al: Ten-year results of the treatment of primary operable breast carcinoma: A summary of 304 patients evaluated by the TNM system. Cancer 38:1001, 1976 49. Schwartz G, Birchansky C, Komamicky L, et al: Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast. Cancer 73:362, 1994 50. Singletary S, McNeese M, Hortobagyi G: Feasibility of breast-conservation surgery after induction chemotherapy for locally advanced breast carcinoma. Cancer 692849, 1992 51. Swain S, Sorace R, Bagley C, et al: Neoadjuvant chemotherapy in the combined modality approach of locally advanced nonmetastatic breast cancer. Cancer Res 473889, 1987 52. Townsend C, Abston S, Fish J: Surgical adjuvant treatment of locally advanced breast cancer. Ann Surg 201:604, 1985 53. Valagussa P, Zambetti M, Bignami P, et al: T3b-T4 breast cancer: Factors affecting results in combined modality treatments. Clin Exp Metastasis 1:191, 1983 54. Whitaker S, Battersby C: The dilemma of stage 111 breast cancer: A study of preoperative radiotherapy. Aust NZ J Surg 47:684, 1977 55. Wingo P, Tong T, Bolden S: Cancer statistics: 1995. CA 458, 1995 56. Zucali R, Uslenghi C, Kenda R, et al: Natural history and survival of inoperable breast cancer treated with radiotherapy and radiotherapy followed by radical mastectomy. Cancer 371422, 1976

Address reprint requests to Frederick C. Ames, MD Department of Surgical Oncology, Box 106 The University of Texas M. D. Anderson Cancer Center 1515 Holcombe Boulevard Houston, TX 77030