Im. J Rdarron Ontology Bd Phy\ Vol. Pnnted in the U.S.A. All rights resewed.

23, pp.

t .oO

0360-3016/92 $5.00 Copyright C 1992 Pergamon Press Ltd.

949-960

??Clinical Original Contribution

THE EFFECT

OF SYSTEMIC IN LOCALLY

THERAPY ON LOCAL-REGIONAL ADVANCED BREAST CANCER

CONTROL

LORI J. PIERCE, M.D.,’ MARC LIPPMAN, M.D.,2 NOA BEN-BARUCH, M.D.,3 SANDRA SWAIN, M.D.,2 JOYCE ~‘SHAUGHNESSY, M.D.,3 JUDITH L. BADER, M.D.,’ DAVID DANFORTH, M.D.,4 DAVID VENZON, PH.D.~ AND KENNETH H. COWAN, M.D., PH.D.~ ‘Radiation Oncology Branch, ‘Medicine Branch, 4Surgery Branch, and ‘Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and ‘Vincent T. Lombardi, Cancer Research Center, Georgetown University, Washington, DC 20007 One hundred and seven patients with locally advanced breast cancer were prospectively referred for multimodality treatment on protocol using chemohormonal therapy to maximal response followed by local treatment and maintenance therapy. Forty-eight patients (45%) were diagnosed with Stage IIIA disease, 46 (43%) with Stage IIIB inflammatory cancer, and 13 (12%) with Stage IIIB non-inflammatory disease. Induction therapy consisted of cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil with hormonal synchronization using tamoxifen and conjugated estrogens. Local treatment was determined by response to chemotherapy. Patients with a clinical partial response underwent mastectomy followed by local-regional radiotherapy while patients with a clinical complete response were biopsied for pathologic correlation. Those with residual disease received mastectomy followed by radiotherapy while those with a pathologic complete response received radiation only to the intact breast and regional nodes. With a median follow-up of 64 months, patients with IIIA disease had a significantly lower lucal-

regional failure rate compared to IIIB inflammatory patients, with the J-year actuarial local-regional failure rate as only site of first failure 3% for IIIA disease versus 21% for IIIB inflammatory cancer (p = .02), and localregional failure as any component of first failure 12% versus 36% (p = .Ol), respectively. When local-regional failure was analyzed by repeat biopsy, 5/31 (16%) patients with a pathologic complete response treated with radiation only developed a local-regional failure versus 2/53 (4%) with residual disease treated with mastectomy and postoperative radiotherapy. The 5-year actuarial local-regional failure rate as first site of failure was 23% for radiation only versus 5% for mastectomy and post-operative radiotherapy (p = .07). The response to chemotherapy did not reliably predict local-regional control. Both relapse-free survival and overall survival were significantly better for IIIA versus IIIB patients; stratification by repeat biopsy did not, however, significantly affect either relapse-free or overall survival. Breast cancer, Locally advanced, Radiation Therapy, Local-regional

INTRODUCIION

control.

operable disease and IIIB representing those lesions designated categorically inoperable by Haagensen (23), with 5-year local recurrence rates approaching 50% with radical mastectomy and only anecdotal long-term survivors. These patients were often referred for palliative radiotherapy, with local control rates of 28-75% using high dose radiation (1, 6, 8, 13, 19, 31, 43, 47, 52, 56), often resulting, however, in significant local-regional morbidity (6, 47, 49, 56). With the advent of aggressive chemotherapy to address micrometastatic disease (35, 36, 48, 5 l), surgery has re-

Locally advanced breast cancer (LABC) encompasses a heterogeneous group of breast malignancies, with a wide range of projected 5-year local-regional control rates as well as relapse-free and overall survivals (2, 8, 18, 22,26, 46). Using the 1983 AJC staging criteria (5), Stage III breast cancer represents a spectrum of disease from T3 lesions with clinically uninvolved axillary nodes to inflammatory cancer (T&. Stage III has been divided into IIIA and IIIB disease, with IIIA representing clinically Presented, in part, at the 33rd Annual Meeting of the Amer-

authors thank Jan van de Geijn, Ph.D. and Robert Miller, MS. for their kind assistance in the preparation of this manuscript. Accepted for publication 25 February 1992.

Acknowledgement-The

ican Society for Therapeutic Radiology and Oncology, Washington, DC, 4-8 November 199 1. Reprint requests to: Lori Pierce, M.D., National Cancer Institute, Radiation Oncology Branch, Building 10, B3B69, Bethesda, MD 20892. 949

950

I. J. Radiation Oncology 0 Biology 0 Physics

emerged as a component of local treatment in the management of LABC (11, 18, 22, 25, 35, 40, 43, 44). Valagussa et al. of the National Cancer Institute in Milan, Italy (54) sponsored trials of 205 patients with LABC, including T4a-c lesions but excluding inflammatory and N3 disease. Patients were randomized to three cycles of doxorubicin and vincristine (AV) followed by either radical mastectomy or definitive radiotherapy (XRT), with seven additional cycles of AV following local therapy. Among those patients achieving a complete response, isolated local-regional recurrence rates of 20% and 37% were reported after mastectomy and radiotherapy, respectively, at 10 years, with comparable overall survival. Perloff et al. (42) presented the results of the Cancer and Leukemia Group B randomized trial of 113 patients with Stage III breast cancer, excluding N3 disease but including inflammatory lesions. Modified radical mastectomy (MRM) was compared to XRT after three monthly cycles of cyclophosphamide, doxorubicin, 5-fluorouracil, vincristine, and prednisone (CAFVP), followed by two additional years of CAFVP therapy. Nineteen percent of patients experienced a local-regional failure after surgery compared to 27% after XRT, with no major difference in survival at 37 month median follow-up. Klefstrom et al. from Helsinki, Finland (30) randomized operable Stage III patients after MRM to XRT, six cycles of vincristine, doxorubicin, and cyclophosphamide (VAC) or both with or without levamisole immunotherapy. With 5-year minimum follow-up, 8% of the 40 patients receiving postoperative radiotherapy experienced an isolated LRF compared to 45% receiving postoperative chemotherapy alone and 5% receiving the combination of surgery, radiotherapy, and systemic treatment. This trial demonstrated a significant reduction in local-regional failure with the combination of surgery and post-operative radiotherapy, with further improvement in local-regional control with the addition of chemotherapy. As evident by retrospective and prospective data (6,22, 30, 33, 35, 36, 38, 39,40,42,44, 50, 54, 57), a consensus opinion regarding the optimal local-regional management in LABC has not been reached. This report will present the results of a prospective trial at the National Cancer Institute of the National Institutes of Health of 107 patients with locally advanced breast cancer using aggressive chemotherapy and hormonal synchronization, and radiotherapy with or without mastectomy for local-regional control. Patterns of failure in comparable patient groups will be presented with emphasis upon implications for local-regional management in Stage III disease. METHODS

AND MATERIALS

Eligibility criteria Using the 1983 staging criteria of the American Joint Committee on Cancer (5), 106 females and one male pa* Premarin,

Ayerst Laboratories,

Inc.

Volume 23, Number 5, 1992

tient with locally advanced breast cancer were entered in a prospective trial at the National Cancer Institute, National Institutes of Health (NCI,NIH) from April 1980 through March 1988. Forty-eight (45%) were diagnosed with clinical Stage IIIA disease, 46 (43%) with clinical Stage IIIB inflammatory cancer (IBC), and 13 (12%) with clinical Stage IIIB non-inflammatory disease (non-IBC). Stage IV patients included in the protocol were excluded from the current analysis. All pathologic diagnoses were histologically confirmed at the NIH. Patients were excluded with a history of prior cytotoxic therapy or prior malignancy with the exception of basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ. Pre-treatment evaluation Evaluation included complete history and physical examination, CBC, platelet count, urinalysis, serum chemistries, chest X ray, mammogram, bone scan with plain film correlation of abnormal findings, and liver-spleen scan. White cell and platelet counts exceeded 4,000/mm3 and 100,000/mm3, respectively; hepatic and renal panels were within normal limits. Protocol schema The first 12 patients were randomized between two chemotherapeutic regimens with and without hormonal synchronization (Table 1). Patients were randomized to either cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil (CAMF) or CAMF with tamoxifen followed by conjugated estrogens* (CAMFTP). Tamoxifen and estrogens were administered prior to the cell-cycle specific agents methotrexate and 5-fluorouracil. Hormonal synchronization was based upon laboratory data suggesting the reversal of tamoxifen-induced inhibition of breast cancer cell growth by estrogen resulting in increased cell sensitivity to cytotoxic therapy (4 1, 55), and clinical data from metastatic breast cancer patients suggesting an improved disease-free and overall survival among objective responders receiving hormonal synchronization (34). Evaluation of the initial 12 patients in the current trial demonstrated a higher percentage of complete responders with tamoxifen and estrogen; therefore all subsequent 95 patients received a chemohormonal regimen using hormonal synchronization (Table 1). This second regimen reduced the dose of cyclophosphamide from 750 mg/m* to 500 mg/m* and increased the methotrexate dose from 40 mg/m* to 300 mg/m’, accompanied by a Leucovorin rescue of 10 mg/m* orally every 6 hr for six doses starting on day 9. As shown in Figure 1, all patients received induction chemotherapy to maximal clinical response. A clinical complete response (CCR) was defined as the total disappearance of all clinical evidence of disease; a clinical partial response (CPR) was at least a 50% reduction in the size of all measurable tumor areas as determined by the prod-

9.51

Systemic therapy in advanced breast cancer 0 L. J. PIERCEet al.

Table 1. Chemotheraov

reeimens

First I2 patients randomized

C A M F T P

Cyclophosphamide 750 mg/m2 IV day 1 vs Doxorubicin 30 mg/m* IV day 1 Methotrexate 40 mg+/m2IV day 8 5-Fluorouracil 500 mg/m2 IV day 8 Tamoxifen 20 mg days 2-6 Estrogen* 0.625 mg q 12 hr days 7-8

C A M F

T P

Subsequent 95 patients C A M F T P

Cyclophosphamide 500 mgjm2 IV day 1 Doxorubicin 30 mg/m2 IV day 1 Methotrexate 300 mg/m2 IV day 8 5-Fluorouracil 500 mg/m2 IV day 8 Tamoxifen 40 mg days 2-6 Estrogen* 0.625 ma a 12 hr. davs 7-8

dose of 5400 cGy (range 4500-5406 cGy). The technique for field matching has been previously described (33). For patients receiving post-mastectomy radiotherapy, a median dose of 5400 cGy (range 2640-5990 cGy) was delivered to the chest wall and internal mammary nodes via tangential fields using 4MV photons; the supraclavicular fossa received 5400 cGy (2640-6600 cGy) at a depth of 3 cm. For patients who did not undergo a complete axillary dissection, a posterior axillary boost was added to bring the median midplane axillary dose to 5 110 cGy (2640-5806 cGy). Bolus was applied to the chest wall every other day. In patients with inflammatory cancer, bolus was also applied every other day to the intact breast as tolerated. Lung correction was calculated using computerized tomography measurements, as previously described (2 1).

* Premarin, Ayerst Laboratories, Inc. Follow-up evaluation

uct of the maximum length and width. Progressive disease (PD) was defined as an increase of > 25% (at least 2 cm*) of the original lesion or development of any new lesion; no change (NC) represented those patients who failed to qualify as a CR, PR, or PD. For those patients who achieved a CCR, multiple incisional biopsies throughout the breast and at the site of the original primary were performed, directed by physical examination and the pretreatment mammogram. The pathologic response determined local therapy. If patients were found, at time of biopsy, to harbor residual disease, local therapy consisted of total mastectomy generally accompanied by axillary dissection, and postoperative local-regional radiotherapy. For pathologic complete responders (PCR), definitive radiotherapy to the breast and regional nodes was delivered. Systemic therapy consisting of CMFJJP was given concurrently with radiotherapy; doxorubicin was deleted. At the completion of local therapy, six additional cycles of chemotherapy (CAMFTP) were administered, with the total dose of doxorubicin not exceeding 525 mg/m*. Radiotherapy The fractionation schemes varied during the period under study. In the earlier years of the protocol, 4400 cGy

in 220 cGy fractions was delivered to the intact breast and internal mammary nodes using tangential fields and 4 MV photons. A photon or electron boost to the original primary tumor volume was then given. In later years, the fractionation scheme was changed to either 5000 cGy in 200 cGy fractions or, in the majority of patients, 5400 cGy in 180 cGy fractions, with a subsequent boost. The median dose delivered to the original tumor volume was 6000 cGy (range 5220-6660 cGy). An oblique supraclavicular field was delivered anteriorly, at 10 degrees off the vertical, with the dose prescribed at 3 cm depth; the median dose delivered was 52 10 cGy (range 4400-5400 cGy). A posterior axillary boost was provided to bring the midplane dose to the clinically negative axilla to a median

While on therapy, weekly CBC, platelet counts, and serum chemistries were obtained. Prior to each cycle of chemotherapy, all patients were examined to assess clinical response. At the time of maximal response, a repeat mammogram was obtained. At the completion of all therapy, patients were followed every 4 months with physical exam, CBC, serum chemistries, and annually with mammogram, bone scan, chest x-ray, and liver scan. Cosmesis

Thirty-one charts of patients treated with breast preservation were retrospectively reviewed for cosmetic analysis; information was available to assess cosmesis in 25 women. In ge&ral, the cosmetic result was stated by the examining physician. In other cases, cosmesis was retrospectively assigned if adequate information and/or pictures were available. Cosmesis was determined with regard to breast size, breast edema, retraction, fibrosis, and skin changes including telangiectasia and pigmentation. Cosmetic scores were assigned using criteria previously defined ( 16): excellent-treated breast almost identical to the untreated breast; good-minimal difference between

Chemotherapy / Clinical CR

to best response \

Clinical

PR/NC

Rebiopsy Pat holkal

Tumor

4 XRT + Chemo Additional

1 4 Mastectomy+XRT+Chemo Chemotherapy

Fig. 1. Treatment schematic for locally advanced breast cancer protocol. CR = Complete response; PR = Partial response; NC = No change; XRT = Radiation Therapy; Chemo = Chemotherapy.

952

I. J. Radiation Oncology 0 Biology 0 Physics

the treated and untreated breast; fair-obvious difference between the treated and untreated breast but without major distortion; poor-major functional and esthetic sequelae in the treated breast. Data analysis With a median follow-up of 64 months (range 34- 130 months), 107 patients were analyzed for relapse-free and overall survival. Six patients did not receive local-regional therapy due either to progression of disease on chemotherapy or refusal of local treatment; they were excluded from local analysis. Of the 10 1 patients treated with localregional therapy, 53 had a positive biopsy and underwent mastectomy and postoperative radiotherapy and 3 1 had a negative biopsy and were treated with radiation alone. The remaining 17 patients were either not biopsied prior to local therapy or did not follow the protocol guidelines for biopsy-directed local therapy. These patients are included in the local-regional analysis by stage but, due to protocol deviation, are excluded in the local-regional analysis by biopsy. A local-regional-only failure as first site of failure was defined as a breast/chest wall only, regional only, or simultaneous breast/chest wall and regional failure in the absence of distant metastases. A regional failure was defined as a failure in the axillary, infraclavicular, supraclavicular, or internal mammary nodal regions. A local-regional failure as a component of first failure included all local, regional, or local-regional failures whether isolated or concurrent with distant failure. Any local-regional failure included all local, regional, or local-regional failures throughout the follow-up period despite prior, concurrent, or subsequent distant failures. A patient was considered relapse-free if continuously free of disease from the start of induction chemotherapy to the last follow-up visit. Patients considered without evidence of disease (NED) at last observation included all relapse-free patients and those with local and/or regional failures successfully salvaged by the last observation period. All deaths were scored as survival failures including patients NED at time of death. Comparisons of clinical characteristics were performed using a Fisher’s exact test. Univariate and multivariate analyses for local-regional control in patients treated with radiation only were performed using a stepwise Cox regression model ( 15). Local-regional, relapse-free, and overall survival curves were generated using the KaplanMeier technique (29) with comparisons between the curves calculated by the log-rank test (32, 37). RESULTS Clinical characteristics by stage Clinical characteristics of the 107 patients were compared by stage (Table 2). Equal numbers of patients with IIIA disease were pre- and post- menopausal; among BIB patients, however, the majority (68%) were postmeno-

Volume 23, Number 5. 1992

pausal (p = .0002). The percent of ER positive tumors was comparable between IIIA and IIIB patients. Seventysix percent of patients with IIIB disease presented with clinically positive nodes compared to 67% of IIIA patients (p = .38). The median age at presentation varied with stage, with IIIA patients presenting at a younger age compared to IIIB IBC and IIIB non-IBC patients. The median number of cycles to maximal response was five for IIIA and IIIB inflammatory patients (range 2-11 cycles) and four for IIIB non-inflammatory disease (range 3- 10). Clinical and pathological response The maximal clinical and pathologic response to induction chemotherapy was compared by stage. Objective clinical responses were obtained in 92% of patients with IIIA disease versus 98% with inflammatory cancer and 85% with IIIB non-inflammatory disease, with objective clinical complete responses in 50%, 57%, and 3 1% of patients with IIIA, IIIB IBC, and IIIB non-IBC disease, respectively. Of those patients with clinical complete responses, 58% with IIIA or IIIB inflammatory disease and 50% (2/4) with IIIB non-inflammatory cancer were pathologic complete responders (PCR), representing 29% (31/107) of the initial study group and 37% (31/84) of those patients biopsied. Local-regional failure by stage One hundred and one patients were analyzed for localregional control, with 441101 (44%) having IIIA disease, 44/ 10 1 with IIIB inflammatory cancer, and 13/ 10 1 ( 12%) with IIIB non-inflammatory disease. Fifty-seven percent of IIIA patients and 48% of IIIB IBC patients were treated with mastectomy and post-operative radiotherapy, while 32% with IIIA disease and 34% with IIIB IBC received radiation only. Eleven percent of IIIA patients were either not biopsied or were protocol violations versus 18% for IIIB IBC, and 31% for IIIB non-IBC (Table 3). Patients with IIIA disease had significantly fewer localregional failures compared to IIIB IBC or non-IBC disease, with the 5-year actuarial LRF as first site of failure 3% for IIIA versus 21% for IIIB IBC (p = .02) and 33% for BIB non-IBC (p = .03) (Table 4). Local-regional failure as a component of first failure was also significantly less for IIIA compared to IIIB IBC, with the 5-year actuarial failure rate of 12% versus 36%, respectively (p = .O1). The 5-year actuarial failure rate for any local-regional occurrence was 15% for IIIA vs 39% for IIIB IBC (p = .02). Although a trend toward increased local-regional failure as component of first failure or any LRF was seen in IIIB non-IBC compared to IIIA disease, statistical significance was not reached, most likely due to small patient numbers. Clinical characteristics by biopsy Eighty-four patients in whom pathologic information was obtained at biopsy were compared with respect to menopausal status, clinical T and N stage, estrogen receptor positivity, number of cycles to best response, and

Systemic therapy in advanced breast cancer 0 L. J. PIERCE

953

et al.

Table 2. Clinical characteristics by stage IIA

No. of patients Premenopausal Postmenopausal T, TZ T3 T4 No NI N2 N3

ER positive ER negative ER unknown Number of cycles to best response Median Range Age (years) Median Range

IIB non-inflam

IIB inflam

No.

(o/o)

No.

(%)

No.

(%)

48 24 24 1 2 45 0 16 16 16 0 16 20 12

(50) (50) (2) (4) (94) (0) (33) (33) (33) (0) (33) (42) (25)

46 15 31 0 0 0 46 11 22 9 4 13 15 18

(33) (67) (0) (0) (0) (100) (24) (48) (20) (9) (28) (33) (39)

13 4 9 0 1 3 9 3 2 2 6 5 4 4

(31) (69) (0) (8) (23) (69) (23) (15) (15) (46) (38) (31) (31)

5 2-11

5 2-11

4 3-10

48 26-17

53 33-73

57 27-68

Inflam = Inflammatory breast cancer; Non-inflam primary tumor status; N = Clinical nodal status.

= Non-inflammatory

breast cancer; ER = Estrogen receptor; T = Clinical

radiation only. The 5-year actuarial local-regional failure rate as first site of failure was 5% for positive biopsy patients compared 23% for those with a negative biopsy (p = .07) (Figure 2a). Local-regional failure as component of first failure was 15% for positive biopsy patients compared to 33% for negative biopsy patients (p = . 1) (Figure 2b), and any local-regional failure,,was 18% and 32%, respectively (p = .2). Of the eight patients who developed a local-regional failure as component of first failure, six had a breast recurrence, one had a breast and axillary failure, and one had an axillary failure in the absence of a breast recurrence. Two of the five patients with an isolated local (breast) failure after radiation only were surgically salvaged by mastectomy. One of the two patients salvaged was lost to follow-up at 17 months at which time she was NED; the second patient was rendered disease-free at the chest wall but subsequently developed contralateral inflammatory cancer. The remaining three patients developed diffuse

age (Table 5). The groups were comparable in every category with the exception of estrogen receptor status, with more patients in the positive biopsy group being ER positive compared to those with a negative biopsy (p = .O16). Subgroup analysis of patients with T4 disease identified 15/3 1 (48%) of negative biopsy patients to have inflammatory disease compared to 2 l/53 (39%) with a positive biopsy (p = .6). Local-regional failure by biopsy

Despite the presence of residual disease in the breast at completion of the induction chemotherapy, positive biopsy patients treated with mastectomy and post-operative radiotherapy had fewer local-regional failures than patients without residual tumor treated by definitive radiotherapy. Two of 53 patients (4%) with residual disease treated with mastectomy and post-operative radiotherapy developed an isolated LRF compared to 5/31 patients (16%) with a pathologic complete response treated with

Table 3. Stage by biopsy result Repeat biopsy (+) biopsy

(-) biopsy

Unknown

Stage

No.

(%)

No.

@)

No.

(%)

Total

III* IIIB inflam IIIn non-inflam

25 21 7

1:;;

14 15 2

i::;

5 8 4

(11) (18) (31)

44 44 13

Inflam = Inflammatory

(54)

breast cancer; Non-inflam

= Non-inflammatory

(15) breast cancer.

954

1. J. Radiation Oncology 0 Biology 0 Physics

Volume 23, Number 5, 1992

Table 4. 5-year actuarial local-regional failure by stage

Local/regional only, first site of failure Local/regional as component failure Any local/regional failure

Inflam = Inflammatory

of first

A IllA %

B IIIB Inflam %

C IIIB Non-inflam %

3

21

33

12

36

39

15

39

31

breast cancer: Non-inflam

= Non-inflammatory

breast and skin involvement and could not be salvaged. The ultimate local-regional failure as first site of failure including salvage, was 5% for positive biopsy patients (M + XRT) versus 13% for negative biopsy patients (XRT only) (p = .3), and LRF as component of first failure 15% and 24%, respectively (p = .38). Prognostic factors were analyzed as predictors of localregional failure in patients treated with radiation only. Fractionation schemes were compared using the Extrapolated Response Dose (ERD) from the linear quadratic model introduced by Barendsen (4) to select biologically isoeffective regimens:

where D = total dose and d = dose/fraction. Taking cu//3= 10 Gy, ERD becomes 72 Gy for D = 6000 cGy and d = 200 cGy. Using an ERD of I 72 versus > 72, the fractionation schedules for the total dose to the tumor bed were compared. Other potential prognostic variables including clinical T size (T3 vs T4), clinical N size (N, vs N1_3),stage (BIB IBC vs IIIA), age (I 40 vs > 40) menopausal status, and estrogen receptor status were compared using a Cox regression analysis. The only variable found to independently predict for local-regional failure was clinical T size, with T4 lesions having a significantly greater risk of failure than T3 tumors (p = .05).

A A A A A A

vs vs vs vs vs vs

p-value

B C B C B C

.02 .03 .Ol .l .02 .3

breast cancer.

mastectomy and radiotherapy compared to 50% with radiotherapy alone. The time course to failure was compared. For patients treated with radiation only who developed a local-regional failure as component of first failure, the median time to local-regional failure after completion of all therapy was 22 months, with 75% (6/8) of failures by 2 years. The median time to distant failure was 14 months, with 82% (9/ 11) manifesting a metastasis as component of first failure by 2 years. The median time to local-regional failure in patients treated with surgery and post-operative radiotherapy was 12 months, with 83% (5/6) by 2 years. Median time to distant failure was 15 months, with 79% (19/24) by 2 years.

Relapse-free and overall survival The 5-year actuarial RFS was significantly better for patients with IIIA disease compared to IIIB IBC or IIIB Table 5. Clinical characteristics by biopsy

No. of patients Premenopausal Postmenopausal T, TZ T3

Patterns offailure The patterns of first failure of the positive biopsy (M + XRT) and negative biopsy (XRT only) patients were contrasted (Table 6). Among both patient cohorts, distant failure was the predominant pattern of first failure, with 38% of patients with a positive biopsy developing isolated distant metastases as first site of failure and 45% having distant metastases as a component of failure vs 26% and 36%, respectively, for negative biopsy patients. Conversely, isolated local-regional failure was less frequent in the positive biopsy group, with 4% of patients having an isolated LRF and 11% with LRF as component of first failure; corresponding values for negative biopsy patients were 16% and 26%, respectively. Local-regional failure accounted for 23% of failures in patients treated with

Mantelhaenszel

T4 No N, N2 N3

ER positive ER negative ER unknown Number of cycles to best response Median Range Age (years) Median Range

Biopsy (+)

Biopsy (-)

No.

(%)

No.

53 19 34 1 2 23 27 15 19 15 4 23

(36) (64) (2) (4) (43) (51) (28) (36) (28) (8) (43)

19

(36)

1:

(45)

11

(21)

12

(39)

31 14 17 0 1: 17 11 12 8 0

(%)

p-value*

(45) (55) (0) (0) (45) (55) (36) (39) (26) (0) (16)

NS NS

NS

.016

5 2-11

5 2-11

NS

52 32-77

52 27-72

NS

* Fisher’s exact test. NS = Not significant; T = Clinical primary tumor status; N = Clinical nodal status.

(+) Xsdors

OP 09

00 x4-8

06 oat

956

1. J. Radiation Oncology 0 Biology 0 Physics Table 6. Patterns

of first failure

%

%

Site of failure

No.

total

failures

(+) Biopsy/(M + XRT) Local/regional Distant L/R and DM

2 20

4 38

8 71

4

7

1.5

5 8

16 26

31 50

3

10

19

(-) Biopsy/(XRT only)

Local/regional Distant L/R and DM

M + XRT = Mastectomy and postoperative radiation therapy; XRT = Radiation therapy only; L/R = Local/regional; DM = Distant metastases.

5 years), the difference was not statistically significant (p = .15).

Survivals were compared by biopsy result (Table 7). Patients with a positive biopsy (M + XRT) had a 5 year actuarial RFS of 46% versus 42% for the negative biopsy (XRT only) group (p = 1 .O). Overall survival also did not significantly differ, with the 5-year actuarial survival for positive biopsy patients being 46% vs 6 1% for those with a negative biopsy (p = .3). Cosmesis and complications

Twenty-five patients treated locally with radiation only were assessed for cosmetic outcome. With a median follow-up of 49 months (range 8- 120 months), 44% ( 11/25) had a good cosmetic outcome, 44% had a fair result and 12% (3/25) had a poor cosmetic outcome. All patients with poor cosmesis presented with inflammatory disease. Patients with a fair to poor cosmetic result developed marked fibrosis and retraction at the treated breast with severe volume loss. The three patients with a poor result had breast exams difficult to follow, resulting in frequent biopsies to rule out recurrent tumor and, in one patient, mastectomy for severe breast pain. Four of twenty-five patients (16%) developed rib fractures and 2/25 (8%) developed matchline fibrosis. DISCUSSION This series presents a unique opportunity to assess the ability of chemotherapy to cytoreduce local-regional disease and to contrast two local therapies in comparable patient groups. Pathologic review of biopsies taken from clinical complete responders revealed 57% of the biopsy specimens to be pathologically without evidence of disease, representing a 29% pathologic complete response rate in the series overall and 37% of those patients biopsied. The pathologic complete response rate reported in this series is higher than in other series documenting histopathologic complete remission after neoadjuvant chemotherapy (7, 17). Feldman et al. (17) from M. D. Anderson reported a 6.7% PCR in mastectomy specimens after three cycles of FAC chemotherapy. Bonadonna et

Volume 23, Number 5, 1992

al. (7) found a 4% pathologic CR after three to four cycles of either CMF, CAF, or FE(epirubicin)C using quadrantectomy or mastectomy. The increased pathologic complete response in the current series may, in part, reflect an improved outcome using chemotherapy to maximal clinical response rather than a fixed number of induction cycles, with a median number of five cycles used in this series. It may also reflect, however, an overestimate of the true pathologic complete response because of sampling error using incisional biopsy since only mastectomy can accurately assess complete pathologic outcome. Our results show a significantly improved local-regional control rate for Stage IIIA disease compared to Stage IIIB inflammatory and non-inflammatory disease, with 5-year actuarial local-regional control of 97% for IIIA disease versus 79% for IIIB IBC and 67% for IIIB non-IBC. Strom et al. (50) found similar results when comparing IIIA and IIIB non-inflammatory patients treated with mastectomy and post-operative radiotherapy, with IO-year actuarial local-regional control rates of 88% for IIIA and 74% for IIIB non-IBC (p < .OO1). Hortobagyi et al. (26) also found comparable results when analyzing the M. D. Anderson experience with multimodal therapy. No patients with IIIA disease developed a local-regional failure; 2 1% of the IIIB non-inflammatory patients developed either a chest wall or regional recurrence as first site of disease. Retrospective studies have frequently selected patients with bulky local-regional disease for radiation only, reserving surgery as a component of therapy for patients with less extensive disease (6, 8, 13, 19,23, 52). The current series, however, demonstrates a reverse selection bias in favor of radiotherapy, with patients having no residual tumor at biopsy receiving radiation only and those with residual disease having mastectomy and post-operative radiotherapy. Despite this selection bias, local control was worse for the radiation-only group compared to those with residual disease treated with combination local therapy. The increased local failure rate despite negative biopsies presumably reflects sampling error, leaving undetected disease remaining in the breast. Brun et al. (9) found similar results in a prospective study of 23 patients with nonmetastatic inflammatory disease. Thirteen women received external beam and interstitial irradiation to the intact breast and ten received preoperative radiotherapy Table 7. Five year actuarial

Stage IHA Stage IIIa inflam Stage IIIa non-inflam Positive biopsy Negative biopsy

relapse-free

and overall survival

No. of patients

RFS %

OS %

48 46 13 53 31

55 33 31 46 42

61 36 31 46 61

RFS = Relapse-free survival; OS = Overall survival; Inflam = Inflammatory breast cancer; Non-inflam = Non-inflammatory breast cancer.

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followed by mastectomy. Despite a mean residual tumor size of 1.4 cm among patients treated with breast preservation versus 4.3 cm prior to mastectomy, local control was improved among patients receiving mastectomy, with 44% experiencing a local-regional failure after radiationonly compared to 20% after combined local therapy. Although patients treated with radiation-only in the current series were comparably matched with respect to T and N status with patients treated by mastectomy and postoperative therapy, 48% of patients treated with radiation alone presented with inflammatory disease compared to 39% treated with combined local therapy, which may have contributed to the difference in local-regional control. While surgical salvage has been successful in the majority of patients with early stage breast cancer who develop an isolated breast recurrence (20), the rate of salvage and subsequent local-regional control in locally advanced disease is unclear. Three of the five women in the current series who experienced an isolated breast failure after radiation alone could not be surgically salvaged because of diffuse breast and skin involvement. As an uncontrolled local recurrence represents a devastating therapeutic failure, the effectiveness of surgical salvage in advanced staged disease is an important endpoint. Further follow-up of the current series may provide additional information regarding success of salvage in Stage III disease treated locally with radiation only. Prognostic variables were analyzed as predictors for local-regional failure among patients treated with breast preservation. Clinical T stage at presentation was the only factor to significantly predict local failure; the extrapolated response dose (ERD), clinical nodal status, stage, age, menopausal status, and estrogen receptor status did not significantly impact upon local control. Others (6,13) have also found T stage to predict for local failure, with improved control with T3 lesions compared to Tq disease. Thomas et al. (52) found T stage to be an important predictor of failure, with a 5-year local control rate of 40% for inflammatory lesions treated with radiation only versus 54% for locally-advanced non-inflammatory lesions and 85% for tumors less than 4 cm. Bruckman et al. (8) did not find a correlation between size and T stage and local control; dose, however, was generally increased for larger tumors and lesions were excised if technically possible. Both of these factors may have lessened any effect of T stage upon local control. Many series have suggested a dose-response for locally-advanced disease ( 1, 8, 13, 19, 43) with improved local control using higher doses of radiation. Because of the narrow range of doses used in the current study, a dose-response for local-regional control could not be established. The cosmetic result in 25 women treated with breast preservation was assessed; 44% had a good cosmetic outcome, 44% had a fair result, and 12% were judged to have a poor cosmetic result. These findings are in agreement with other locally-advanced series (43, 47). Pierquin (43) noted a very good cosmetic result in 45% of women with

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T3 lesions compared to similar cosmesis in over 75% of patients with T, and T2 lesions. Sheldon (47) found a 56% good-to-excellent result using primary radiation therapy for locally advanced disease, with 25% of women having a fair outcome and 19% having a poor outcome. These results compare unfavorably, however, to early stage breast cancer results in which cosmesis is good-to-excellent in 80-90% of women at 5 years (16, 45). The reasons for these differences are multifactorial. To boost the original tumor bed in locally advanced disease may require treatment of a large volume of breast tissue to doses exceeding cosmetically acceptable levels. Chemotherapy is generally administered to patients with advanced stage disease, often concurrently with radiation, which, as shown by others, may predispose to an adverse cosmetic outcome (16,45, 47). Although doxorubicin was withheld during the administration of radiation on the present series, methotrexate was given concurrently which may have contributed to the suboptimal cosmetic results. Bolus is often applied to the skin to decrease the skin-sparing effect of megavoltage radiation in patients with Stage III disease. As bolus increases the dose to the skin, it may also increase the risk of telangiectasia and fibrosis, resulting in an undesirable cosmetic outcome; it must be judiciously applied. The patients in the current series with a poor cosmetic result were treated with bolus because of presentation with inflammatory disease. Total dose, boost volume, technical factors, and modification of concurrent chemotherapy must be considered if breast preservation is to be an option in the management of locally advanced disease. Alternative strategies which have been considered as a means of breast preservation include hyperfractionated radiotherapy, neutron therapy, and the use of radiosensitizing agents. Hyperfractionated radiotherapy offers the theoretical advantage of increased cell kill of rapidly cycling clonogens relative to normal tissue while decreasing treatment related morbidity in late reacting tissues. Earlier reports (10, 14) suggested an improvement in local-regional control using hyperfractionated radiotherapy compared to results using standard fractionation in patients with inflammatory cancer. A recent report by Thorns et al. (53) did not demonstrate a benefit in local control using post-mastectomy hyperfractionated radiotherapy; late complications were, however, less common. Dose escalation may improve these results. Experience with neutrons in locally advanced breast cancer has been reported (12, 24). Catterall et al. (12) achieved a 95% complete response rate with neutron therapy. However, late reactions included severe breast telangiectasia in 100% of patients and 18% necrotic ulcer formation. Halpem et al. (24) reported a 32% complete response rate using a neutron beam or a mixed neutron and photon beam. Late toxicity was severe with 2 1% of patients experiencing breast or chest wall ulceration. Among those receiving axillary neutron therapy, 33% developed severe edema and 50% developed brachial plexopathy. The treatment-

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related morbidity led the authors to advise against the use of neutron therapy for locally advanced breast cancer. Experience with radiosentizers in breast cancer has been limited. Baillet et al. (3) used misonidazole with brachytherapy and hypofractionated radiotherapy in 38 breast cancer patients. Complete response rates were improved compared to those not receiving the drug (74% vs 60%, p = ns.); local control results were not discussed. Our limited clinical experience with halogenated pyrimidine sensitizers has shown intense skin reactions in the tangenting portions of the field. Other agents may be more promising. Recent series have examined the use of neoadjuvant chemotherapy to obviate the need for mastectomy in locally advanced disease (2, 7, 9, 27, 28). Jacquillat et al. (28) used an induction regimen of vinblastine, thiotepa, methotrexate, 5fluorouraci1, doxorubicin and prednisone (VTMFAP) followed by hypofractionated Cobalt-60 radiotherapy, an iridium implant and adjuvant VTMFAP. With median follow up of 62 months, the local-regional recurrence rate was 18% for T3 disease and 19% for Tq disease among the 113 patients studied. Eight of the 15 local-regional failures included skin involvement. Thus, not all radiation failures could be surgically salvaged. In the report by Bonadonna et al. (7) cyclophosphamide, 5fluorouracil, and either methotrexate, doxorubicin, or epirubicin were administered as primary therapy for tumors measuring 3 cm or greater. Local therapy consisted of quadrantectomy and breast radiotherapy when post -induction tumor volume was less than 3 cm. Mastectomy was performed when residual disease measured 3 cm or greater. Using this schema, breast preservation was possible in 8 1% of patients studied. Seventy-nine percent of the patients enrolled in this trial, however, presented with lesions less than or equal to 5 cm, and 97% had either No or N, disease. Many of these patients would have been offered breast preservation in American cancer centers as this represents a predominantly Stage II series. Eighty-six percent of women diagnosed with tumors up to 5 cm experienced tumor reduction to 3 cm or less after three to four cycles of neoadjuvant therapy compared to 59%

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of patients presenting with lesions greater than 5 cm. This may reflect the need for additional cycles of chemotherapy in patients presenting with increased tumor bulk rather than a relative chemoresistance of large tumors. Hortobagyi et al. (27) prospectively evaluated the use of 4 cycles of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) as neoadjuvant therapy in a series of 128 patients. Forty-three percent presented with Td disease, 37% with T3 lesions, 15% with Tz tumors and 5% with T,_, disease. Patients achieving a complete or partial response who met specific criteria for breast preservation underwent segmental resection, axillary dissection, local radiotherapy, and adjuvant chemotherapy; those with less of a response underwent mastectomy, axillary dissection, and adjuvant chemotherapy. Using these selection criteria, only 27% of the patients overall were candidates for breast preservation. Breast conservation rates were 100% for patients presenting with T,_, disease and 46% for T2 disease, decreasing to 23% for T3 and 16% for T4 disease. Only one local failure has been reported; median follow-up however, is only 8.5 months. In the current series, multivariate analysis of factors for local-regional failure among patients treated with radiation only identified T4 disease as the only factor significantly affecting local-regional control. While it appears from these collective data that selected patients with locally advanced disease may be candidates for breast preservation, strict criteria for patient selection and durability of local-regional control remain study questions to be addressed in prospective randomized trials. The predominant failure pattern and cause of death in locally advanced breast cancer remains distant dissemination, with metastatic disease accounting for 92% of first failures in the current series among patients treated with surgery and radiotherapy and for 69% of the failures in patients treated locally with radiation alone. Therefore, despite differences in local control, relapse-free and overall survival were not significantly altered. As more effective systemic therapy becomes available, the argument for maximal local control becomes more compelling. These data demonstrate higher local-regional control using the combination of surgery and post-operative radiotherapy.

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