the role of mastectomy in patients with stage i-ii breast cancer presenting with gross multifocal or...

Inr .I Rudmmn Oncology Bfol Phy.7, Vol. 27, pp 567-573 0360.3016193 $6.00 + .OO Prmtcd I” the U.S.A. All nghts reserved. Copyright 0 1993 Pergamon Press Ltd.

??Clinical Original Contribution

THE ROLE OF MASTECTOMY IN PATIENTS WITH STAGE I-II BREAST CANCER PRESENTING WITH GROSS MULTIFOCAL OR MULTICENTRIC

DISEASE OR DIFFUSE MICROCALCIFICATIONS

BARBARA FOWBLE, M.D.,’ I-TIEN YEH, M.D.,2 DELRAY J. SCHULTZ, PH.D.,~ LAWRENCE J. SOLIN, M.D.,’ ERNEST F. ROSATO, M.D.,4 LORI JARDINES, M.D.,4 JOHN HOFFMAN, M.D.,’ BURTON EISENBERG, M.D.,5 MARISA C. WEISS, M.D.6

AND GERALD HANKS, M.D.6

‘Department of Radiation Oncology, *Department of Pathology, 4Department of Surgery, University of Pennsylvania School of Medicine; ‘Department of Statistics, University of Pennsylvania Cancer Center; ‘Department of Surgery,

Fox Chase Cancer Center; and 6Department of Radiation Oncology, Fox Chase Cancer Center and Network

Purpose: Women with Stage I-II invasive breast cancer who present with gross multicentric disease or diffuse microcalcifications have a significant risk of breast recurrence when treated with conservative surgery and radiation. The purpose of this report is to present the results of mastectomy in this group of patients. Methods and Materials: Between 1982 and 1989, 88 patients with clinical Stage I-II breast cancer who presented with clinical and mammographic evidence of gross multicentric disease or diffuse microcalcifications underwent modified radical mastectomy: Median followupwas 4 years for the 57 patients with gross multicentric disease and 5.6 years for 31 patients with diffuse microcalcifications. At the time of mastectomy, 42% of patients were found to have positive axillary nodes. Following mastectomy, 15 patients received post mastectomy radiation and 35 patients received adjuvant systemic chemotherapy. Results: When compared to a group of 1295 patients with unifocal, Stage I-II breast cancer, treated with conservative surgery and radiation during the same time period, patients with gross multicentric disease and diffuse microcalcifications had a significantly higher incidence of 2 4 positive nodes, patients with gross multicentric disease had a lower incidence of positive resection margins following mastectomy and patients with diffuse microcalcifications were younger. The 5-year actuarial risk of an isolated local-regional recurrence was 8% for patients with gross multicentric disease or diffuse microcalcifications and 7% for patients with unifocial disease. Patients with gross multicentric disease or diffuse microcalcifications and z 4 positive axillary nodes who did not receive post mastectomy radiation had an increased risk for local regional recurrence. There were no significant differences in the 5-year actuarial overall or relapse-free survival (88% and 73% gross multicentric disease, 97% and 86% diffuse microcalcifications and 90% and 79% unifocal disease), freedom from distant metastasis (76% gross multicentric disease, 90% diffuse microcalcifications, 86% unifocal disease) or incidence of contralateral breast cancer (10% gross multicentric disease, 13% diffuse microcalcifications, 8% unifocal disease) among the three groups. Conclusion: The present study demonstrates no increased risk of local-regional recurrence in patients with gross multicentric disease or diffuse microcalcifications undergoing mastectomy in contrast to the increased risk of breast recurrence in patients with gross multicentric disease undergoing conservative surgery and radiation. Indications for post mastectomy radiation include 2 4 positive nodes or close or positive surgical margins. Despite a significantly higher incidence of 2 4 positive nodes, patients with gross multicentric disease and diffuse microcalcifications have a 5-year actuarial overall and relapse-free survival comparable to a group of patients with unifocal disease treated with conservative surgery and radiation.

Breast cancer, Gross multicentric disease, Diffuse microcalcifications, Mastectomy.

INTRODUCIION

The presence of gross multicentric or multifocal disease (i.e., the clinical or mammographic presentation of two or more discrete tumors in the same breast) or diffuse microcalcifications in patients with otherwise clinical

Stage I or II breast cancer has been considered a relative contraindication to conservative surgery and radiation (6, 22). Pathologic review of mastectomy specimens at the University of Pennsylvania has revealed extensive residual disease in three or four quadrants of the breast following biopsy in 50% of these patients (7). This finding of a sig-

Reprint requests to: Barbara Fowble, M.D., Dept. Radiation Oncology, Hosp. Univ. Pennsylvania, 3400 Spruce St., Phila- delphia, PA 19 104.

Accepted for publication 8 April 1993.

567

568 1. J. Radiation Oncology 0 Biology 0 Physics

nificant residual tumor burden correlates well with the relatively high breast recurrence rates reported in patients with gross multicentric disease who have undergone conservative surgery and radiation. Leopold rt uf. (16) reported a breast failure in 4 of 10 patients with gross multicentric or multifocal disease who underwent excision of their primary tumors followed by radiation. In contrast, 11% of 707 patients with unifocal disease developed a recurrence in the treated breast. The authors also noted a higher incidence of isolated regional node failure in patients with macroscopically multiple tumors (20%) compared to those with single lesions (1 W). Kurtz ef al. (12) reported a 36% incidence of breast recurrence in 22 patients with clinical and/or mammographic evidence of multiple tumors in the breast. Fifty-six (11%) of 525 patients with unifocal tumors experienced a recurrence in the treated breast. Local recurrences in patients with macroscopic multiple tumors were more often in a sep- arate quadrant or more diffuse than those with unifocal disease. Based on these observations, mastectomy has be- come the recommended treatment for patients with gross multicentric or multifocal disease or diffuse malignant appearing calcifications.

A number of pathologic studies have demonstrated microscopic multicentric foci of cancer in patients whose clinical or mammographic presentation is that of a single lesion (2, 3, 8, 10, 14, 15, 17, 19, 24,26,27,28) and some have correlated the presence of multicentricity with positive axillary nodes ( 17, 19, 26) and a decreased survival (28). However, the outcome of patients undergoing mastectomy with gross multicentric disease or diffuse microcalcifications has not been previously reported. The purpose of this study is to assess the patterns of failure, survival, incidence of contralateral breast cancer, and the role of post-mastectomy radiation in patients with gross multicentric or multifocal disease or diffuse microcalcifications who have undergone mastectomy with or without adjuvant therapy at the University of Pennsylvania and Fox Chase Cancer Center. Their outcome will be compared to that of a group of Stage I-II breast cancer patients with unifocal disease treated with conservative surgery and radiation.

METHODS AND MATERIALS

Between 1982 and 1989, 88 patients with clinical Stage I-II (1) breast cancer presenting with clinical or mammographic evidence of gross multicentric or multifocal disease (GMD) or diffuse microcalcifications (DM) underwent modified radical mastectomy at the University of Pennsylvania or Fox Chase Cancer Center. Patient characteristics are presented in Table 1.

GMD Putient and treatment characteristics. There were 57

patients in this group with a median age of 54 years (range 29-89). Fifty-two of the 57 patients had clinical and/or mammographic evidence of more than one discrete tumor in the breast. Detection was by clinical examination only

Volume 27, Number 3. I993

Table I. Characteristics of patients with GMD or DM

GMD DM

Total no. pts. Median age (range) Median no. gross lesions

(range) Median size largest tumor

mass (range) Median no. involved

quadrants (range) Histology

DCIS and invasive ductal

Invasive ductal Invasive lobular Invasive ductal and

lobular Other

Estrogen receptor Positive Negative Unknown

Progesterone receptor Positive Negative Unknown

Mastectomy margin Negative Positive/close Unknown

Pathologic nodal status Negative Positive 1-3 24

57 31 54 yr. (29-89) 47 yr. (29-79)

2 (2-5) 2.0 cm

(X-5.0)

1 (O-l) 2.3 cm

(.5-5.0)

1 (l-2) I (l-4)

33 (58%) 13 4

24 (77%) 4 2

1 I 6 0

36 (63%) 8

13

I I (35%) IO IO

24 (42%) II 22

9 (29%) 10 12

53 (93%) 4 0

21 (68%) 6 4

31 (54%) 26 15 I1 (21%)

20 (65%) 11

5 6 (19%)

in three patients, clinical and mammographic evaluation in 38 patients, and mammography alone in 11 patients. Five patients had clinical evidence of a single lesion: however, at the time of biopsy, a second gross nodule was identified pathologically in two patients and two addi- tional gross nodules were identified in three patients. Thirty-seven patients (65%) had two macroscopic lesions, 15 had three, four patients had four, and one patient had five lesions. The median size of the largest tumor focus was 2 cm with a range of 0.8 to 5 cm. Histology revealed ductal carcinoma in situ and invasive ductal carcinoma in 33 patients, invasive ductal carcinoma in 13 patients, invasive lobular carcinoma with or without lobular carcinoma in situ in four patients, invasive ductal and lobular carcinoma in one patient, colloid carcinoma in five patients, and signet ring carcinoma in one patient. The estrogen receptor status was unknown in 13 patients, positive in 36, and negative in eight. The progesterone receptor status was unknown in 22 patients, positive in 24, and negative in 11. At the time of mastectomy, the median number of axillary nodes removed was 17 with a range of 8-59. Thirty-one patients had negative axillary nodes and 26 had positive axillary nodes. The median number of positive nodes was three with a range of l-48. Fifteen patients had l-3 positive nodes, six patients had 4-9 positive nodes, and five patients had 10 or more positive

Stage I-II breast cancer 0 B. FOWBLE el al. 569

nodes. Pathologic assessment of the mastectomy specimen revealed tumor to be confined to one quadrant in 20 patients, two quadrants in 13 patients, three quadrants in seven patients, and four quadrants in six patients. The extent of residual tumor was not assessed in one patient. Four patients had positive or close surgical margins (i.e., I 3 mm).

Adjuvant therapy. Following mastectomy, 6 I % of node positive patients and 19% of node negative patients received adjuvant systemic chemotherapy with or without tamoxifen (Table 2). Twenty patients received CMF chemotherapy (cyclophosphamide, 100 mg/m’, po days l- 14, methotrexate, 40 mg/m’, IV days 1 and 8, and 5- fluorouracil, 600 mg, IV days 1 and 8) for a total of six cycles. Two patients received cyclophosphamide, 100 mg/ m2, po days 1- 14, doxorubicin, 30 mg/m2, IV days 1 and 8, and Sfluorouracil, 500 mg/m2, IV days 1 and 8 (CAF). Ten patients received tamoxifen without chemotherapy, ( 10 mg PO BID). Ten patients received post-mastectomy adjuvant radiation including five node negative patients (three close or positive margins and two negative margins) and five patients with four or more positive nodes. None of the patients with l-3 positive nodes received post-mastectomy radiation. In six patients, the post-mastectomy radiation was combined with adjuvant systemic chemotherapy. In two patients, chemotherapy and radiation were given concurrently, and in four patients, radiation was begun at the completion of all chemotherapy. Radio- therapy was delivered with a 6 Mv linear accelerator and consisted of treatment to the chest wall and regional nodes (supraclavicular -t axilla). A total dose of 5000 cGy was delivered in 200 cGy fractions over a period of five weeks to the chest wall with tangential fields. Bolus was employed every other day. The regional nodes received 4600 cGy in 200 cGy fractions delivered over a period of 41 weeks. The median follow-up for patients with gross multicentric disease from the time of mastectomy was 3.9 years with a range of 0.9 to 9.7 years.

DM Patient and treatment characteristics. Thirty-one pa-

tients underwent mastectomy for mammographic evi-

Table 2. Post-mastectomy adjuvant therapy

GMD DM

Adjuvant RX NO N 1-3 N 24 NO N l-3 N 24

None 22 1 0 17 0 0 Chemo t tamoxifen 3 9 4 2 5 I Tamoxifen 1 5 2 1 0 0 Radiation

Alone 2 0 0 0 0 0 Chemo

f tamoxifen 3 0 3 0 0 5 Tamoxifen 0 0 2 0 0 0

NO = path node negative; N l-3 = path node positive, l-3 positive nodes; N 2 4 = path node positive, 2 4 positive nodes.

dence of a diffuse area of malignant-appearing calcifications. Their median age was 47 years with a range of 29 to 79 years. Twenty-eight of these 3 I patients (90%) also had evidence of a mass lesion. The mass was both palpable and mammographically evident in 13, was detected by mammogram only in four, and was a clinical finding only in 11 patients. The median size of the mass was 2.3 cm with a range of 0.5 to 5 cm. Microcalcifications were confined to a single quadrant in 17 patients, two quadrants in six patients, three quadrants in one, and four quadrants in three patients. The extent of the microcalcifications was described as diffuse without the number of quadrants involved in four patients. Histology revealed ductal carcinoma in situ and invasive ductal carcinoma in 24 patients, invasive ductal carcinoma in four patients, invasive lobular carcinoma in two patients, and invasive ductal and lobular carcinoma in situ in one patient. The estrogen receptor status was unknown in 10 patients, positive in 11, and negative in 10. The progesterone receptor status was unknown in 12 patients, positive in nine, and negative in 10. At the time of mastectomy, the median number of axillary nodes removed was 18.5 with a range of 10-36. Twenty patients had negative nodes, and eleven had positive nodes with a median number of four and a range of 1 to 12. Five patients had l-3 positive nodes, five patients had 4-9 positive and one patient has more than 10 positive nodes. Residual tumor was identified in the mastectomy specimen in 29 patients. In 10 patients this was confined to a single quadrant, in three patients it involved two quadrants, in five patients it involved three quadrants, and in one patient four quadrants. The extent of tumor in the mastectomy specimen was unknown for 10 patients. The margin of resection was close in six patients, negative in 2 1, and unknown in four.

Adjztvant therapy. Post-mastectomy, all node positive patients received adjuvant systemic chemotherapy con- sisting of CMF (seven patients) or CAF (four patients), and two node negative patients received CMF chemotherapy (Table 2). One node negative patient received tamoxifen alone. Five of the six patients with four or more positive nodes received post-mastectomy radiation, and none of the 25 patients with negative nodes or l-3 positive nodes received radiation. The median follow-up for patients with diffuse microcalcifications was 5.6 years with a range of 1.9- 11.9 years.

Outcome. Outcome is presented in terms of local regional recurrence, overall, no evidence of disease (NED), and relapse-free survival (RFS). An isolated local regional recurrence for patients undergoing mastectomy was defined as first site of failure in the chest wall and/or regional nodes without an associated simultaneous distant metastasis. The overall local-regional recurrence rate included patients whose first site of recurrence was within the chest wall and/or regional nodes, with or without simultaneous distant metastasis. An isolated local-regional recurrence in patients undergoing conservative surgery and radiation was defined as first site of failure in the treated breast and/ or regional nodes without associated distant metastasis.

570 1. J. Radiation Oncology 0 Biology 0 Physics

The overall local-regional recurrence rate in this group of patients included patients whose first site of recurrence was within the treated breast and/or regional nodes, with or without simultaneous distant metastasis. For analysis of NED survival, patients were required to be alive and without evidence of disease at the time of last follow-up. For analysis of relapse-free survival, patients were required to be alive and continuously without evidence of disease. Patients who relapsed and subsequently underwent sal- vage therapy and were alive without evidence of disease were considered a failure for relapse-free survival, but not NED survival. Survival curves and actuarial rates of local- regional recurrence were calculated using the Kaplan Meier method (11). Statistical comparisons were per- formed using the Mantel Cox test (18).

For comparison of outcome, a group of 1295 patients with unifocal Stage I-II breast cancer treated with conservative surgery and radiation at the University of Penn- sylvania and Fox Chase Cancer Center between 1982 and 1989 was identified. The median follow-up for this group of patients was 4.3 years with a range of .2-9.8 years. Patient and treatment related characteristics of this group are presented in Table 3.

RESULTS

Patterns of first failure are presented in Table 4. The sites of isolated local-regional recurrence in the four patients with GMD included the chest wall and supraclavicular nodes (one patient), the axilla (one patient), and supraclavicular nodes only (two patients). Two patients with DM experienced an isolated local-regional recur-

Table 3. Comparison of patient and treatment characteristics vs. GMD vs. DM

Unifocal GMD DM D value

Total no. pts. Median follow-up Median age Median clinical tumor size (cm) Histology

Invasive ductal ? DCIS Invasive lobular Other

Estrogen receptor Positive Negative Unknown

Progesterone receptor Positive Negative Unknown

Resection margin Positive/close Negative Unknown

Path nodal status Negative Positive l-3 >4

Chemotherapy ? tamoxifen Tamoxifen alone

1295 57 31 4.3 yr. 3.9 yr 5.6 yr.

54 yr. 54 yr. 47 yr. 2.0 2.0 2.3

1145 (88%) 50

100

46 (81%) 4

29 (94%) i 0

752 (58%) 252 291

601 (46%) 336 358

230 (18%) 742 323

900 (69%) 31 (54%) 395 26 296 I5

99 (7%) I I (20%) 350 (27%) 22 (38%) I54 (12%) IO (17%)

36 (63%) 8

I3

24 (42%) II 22

4 (7%) 53

0

I I (35%) IO IO

9 (29%) 10 I2

6 (19%) 21

4

20 (65%) II

6 (19%) I3 (42%)

I (3%)

.I0

.003

.79

.I4

.I0

.I3

.ooo I

.003

.I0

.I4

Volume 27, Number 3, 1993

Table 4. Patterns of first failure

GMD DM

Total no. pts. First failure

57 31

Isolated local-regional 4 2 Local-regional and distant 2 1 Distant only 5 I

Median interval for local-regional I yr. 3 yr. recurrence (range) (.5-3.8) (.6-3.5)

rence, (one in the chest wall and the other in the supraclavicular nodes). Simultaneous distant metastases were associated with a chest wall and supraclavicular node failure in one patient with GMD and with a supraclavicular recurrence in one patient from each group. The median interval to a local-regional recurrence was 1 year (range .5-3.8 years) for patients with GMD and 3 years (range .6-3.5 years) for patients with DM. Five patients with GMD and one patient with DM developed distant metastases without an associated local-regional recurrence.

The 5-year actuarial risk for an isolated local-regional recurrence is 8% for patients with GMD and 8% for patients with DM. The 5-year actuarial risk for any local- regional recurrence (2 simultaneous distant metastases) is 13% for patients with GMD and 1 1 YO for patients with DM. The incidence of local-regional recurrence as related to pathologic nodal status and the use of post-mastectomy radiation is presented in Table 5. Three of the 4 1 patients (7.5%) with GMD, and two of 25 patients (8%) with DM and negative or l-3 positive axillary nodes who did not receive radiation developed a local-regional recurrence. The 5-year actuarial risk of an isolated or any local-regional recurrence is 2% and 9% for GMD patients and 5% and 10% for patients with DM. For patients with four or more positive axillary nodes, 1 of 10 who received radiation developed a local-regional recurrence compared to three of seven who did not. The 5-year actuarial rates were 10% and 46%, respectively, for an isolated local- regional recurrence and 10% and 46% for any local-regional recurrence. Local-regional recurrence with or without simultaneous distant metastases was also analyzed with respect to the status of the mastectomy resection margin and the use of post-mastectomy radiation. Six patients had a close or positive resection margin (three node negative and three node positive) and received radiation. None of these patients experienced a local-regional re-

Table 5. Crude incidence local-regional recurrence f distant metastases related to post-mastectomy adjuvant

radiotherapy and pathologic nodal status

GMD DM

No XRT XRT No XRT XRT

Node negative 3126 015 l/20 Node positive

l-3 o/15 - 115 - 24 216 115 111 015

Stage I-II breast cancer 0 B. FOWBLE et ul. 571

currence. One of four patients (three node negative, and one node positive) with a close or positive margin who did not receive radiation developed an isolated chest wall recurrence. This patient also had four positive axillary nodes. One of nine patients with a negative margin (two node negative and seven node positive) who received radiation developed an isolated supraclavicular node failure. Seven of 68 patients (10%) with a negative margin and no radiation developed a local-regional recurrence. Local- regional recurrence occurred in four of 39 node negative patients and three of 29 node positive patients. None of the four node negative patients with an unknown margin received radiation and there were no local-regional recurrences in this group.

The 5-year actuarial freedom from distant metastases rate was 82% for all patients with GMD, 82% for pathologic node negative patients, and 8 1% for pathologic node positive patients. For patients with DM, the 5-year actuarial freedom from distant metastases rate was 93% for all patients, 100% for node negative patients, and 79% for node positive patients.

Actuarial overall, NED, and relapse-free survival are presented in Table 6. For all patients with GMD, the 5- year actuarial overall, NED, and relapse-free survival are 88%, 74%, and 73%, respectively. For node negative patients, the corresponding results are 87%, 79% and 76%, and for node positive, 90%, 69%, and 7 1%. For all patients with DM, the 5-year actuarial overall, NED, and relapse- free survival are 97%, 90% and 86%. For node negative patients, the rates are lOO%, lOO%, and 93%, and for node positive patients, 9 l%, 72%, and 72%, respectively.

The five patients whose gross multifocal disease was diagnosed only by pathologic examination were analyzed separately and compared to those whose disease was diagnosed clinically or mammographically. The 5-year actuarial rate of an isolated or any local-regional recurrence was 8% and 14% for patients with clinical GMD and 0% for patients with pathologic GMD. The 5-year actuarial overall, NED, and relapse-free survival rates were 87%, 72%, and 7 1% for patients with clinical GMD and lOO%, 1 OO%, and 100% for patients with pathologic GMD. None of these differences was statistically significant.

A contralateral breast primary occurred either syn-

Table 6. Survival outcome

5-year actuarial %

Overall survival NED RFS

GMD All patients 88 74 13 Node negative 87 79 76 Node positive 90 69 71

DM All patients 97 90 86 Node negative 100 100 93 Node positive 91 72 72

NED = No evidence of disease; RFS = Relapse-free survival.

chronously or metachronously in six of the 57 (10.5%) patients with GMD and four of the 3 1 ( 12.9%) patients with DM. The overall incidence for the entire group was 11% (10/88).

The outcome of patients with GMD and DM was then compared to that of a group of 1295 patients with unifocal clinical Stage I-II breast cancer treated with conservative surgery and radiation during the same time period (1982- 1989). The comparability of the three groups in terms of median age, median clinical tumor size, histology, receptor status, final margin status, pathologic nodal status, and the use of chemotherapy and tamoxifen is presented in Table 3. Statistically significant differences included a younger median age for patients with DM, a higher incidence of positive axillary nodes for patients with GMD, a higher incidence of four or more positive nodes for patients with GMD and DM, and a higher frequency of negative resection margins for patients with GMD. Out- come for the three groups in terms of local-regional recurrence, 5-year actuarial rate of freedom from distant metastases, 5-year actuarial overall and relapse-free survival, and the incidence of contralateral breast cancer is presented in Table 7. There were no statistically significant differences among the three groups for any of these pa- rameters.

DISCUSSION

There is little information regarding the overall frequency of presentation of gross multifocal or multicentric disease in women with early stage breast cancer. Kurtz et al. (12) reported macroscopic multiple tumors in 6 1 of 586 (11%) patients undergoing conservative surgery and radiation at the Marseilles Cancer Institute. However, in the majority of these patients, detection was solely by the pathologist and only 3.7% had clinical and/or mammographic evidence of multiple tumors. Leopold et al. (16) identified 10 patients with macroscopic multiple tumors in a series of 697 patients with early stage breast cancer treated with conservative surgery and radiation at the Joint Center for Radiation Therapy. Eight of these 10 patients had clinical evidence of two or more distinct tumors in the breast. In the present series, 52 of the 57 patients with

Table 7. Comparison of outcome unifocal disease vs. GMD vs. DM

Unifocal GMD DM p value

5 year actuarial % Overall survival 90 88 97 .21 RFS 79 73 86 .43

5 year actuarial % Local-regional recurrence 7 8 8 .89 Local-regional + distant

recurrence 9 13 11 .72 Freedom from distant

metastases 86 76 90 .42 Contralateral breast

cancer % 8 10 13 .56

572 I. J. Radiation Oncology 0 Biology 0 Physics Volume 27. Number 3, 1993

gross multifocal or multicentric disease were detected by tients. Only 10 patients had no residual tumor. The as- clinical examination and/or mammography. During this sessment of the extent of residual disease in patients with same time period, 1295 patients with unifocal tumors un- diffuse microcalcifications was more difficult. A serial derwent conservative surgery and radiation. Based on subgross and correlated mammographic examination was these limited data, it appears that patients with gross mul- not employed and sectioning of the entire area of micro- ticentric or multifocal disease represent less than 5% of calcifications was not guaranteed. Despite these limita- the women diagnosed with early stage breast cancer. In tions, 29 of the 3 1 patients with DM had residual disease contrast, the incidence of microscopic multicentricity or in the mastectomy specimen. However, the extent was multifocality in patients with clinically apparent single unknown in 10. Ten patients had disease apparently con- lesions varies from 9 to 75 percent (2, 3, 8, 14, 15, 17, 19, fined to a single quadrant, and nine patients had disease 24,27, 28) depending upon the definition (3, 10, 14) and involving two or more quadrants. Six patients had final the thoroughness with which the mastectomy specimen resection margins that were close (5 3 mm), suggesting a is examined (2, 14, 15). significant amount of residual disease.

In the present series, significant differences among patients with GMD or DM and those with unifocal disease included a younger age at diagnosis in patients with DM, a higher incidence of negative mastectomy resection margins in patients with GMD, a higher incidence of positive axillary nodes in patients with GMD and a greater frequency of four or more positive nodes in both patients with GMD and DM. Kurtz et al. (12) reported a significantly lower incidence of negative resection margins in patients with macroscopically multiple tumors undergoing conservative surgery and radiation. In the present series, mastectomy achieved negative margins in 93% of these patients. Kurtz et al. ( 12) also reported no significant differences in the incidence of positive axillary nodes in patients with GMD when compared to those with single tumors. Several series (17, 19, 26) have suggested that patients with microscopic multicentricity have a higher incidence of positive axillary nodes while others have failed to confirm such a relationship (3,24,27,28). Similar to Kurtz et al. ( 12) the present series found no significant differences in terms of histology or receptor status. There was no increased prevalence of invasive lobular carcinoma which has been associated with microscopic multicentricity (3, 17). However, Leopold et al. ( 16) and Kurtz et al. ( 12) observed a higher incidence of EIC (extensive intraductal component) positive tumors in patients with GMD. In the present series the extent of the intraductal component was not assessed. However, patients presenting with diffuse microcalcifications were more likely to have an intraductal component in association with an invasive ductal carcinoma. It has been previously reported that the most common clinical presentation of EIC positive tumors is that of mammographic microcalcifications with or without an associated tumor mass (9). Patients with DM in the present series were also significantly younger than those with unifocal disease or GMD. A greater prevalence of EIC positive tumors has been observed in younger women (5, 13, 2 1).

The 5-year actuarial risk of a local-regional recurrence following mastectomy was 13% for patients with GMD and 11% for patients with DM. The 5-year actuarial risk of an isolated local-regional recurrence was 8% for patients with GMD or DM. In contrast, two series (12, 16) have reported an increased risk of breast recurrence in patients with GMD undergoing conservative surgery and radiation. Kurtz et al. (12) identified patients with clinical evidence of GMD or those with three or more macroscopic tumors as having the greatest risk. The risk of a breast recurrence was unrelated to the proximity of the multiple tumors (12). For patients in the present series, mastectomy re- sulted in a risk of local-regional recurrence comparable to that of patients with unifocal disease treated with conservative surgery and radiation. The majority of patients did not receive post-mastectomy radiation and an increased risk of local-regional recurrence was observed only in patients with four or more positive nodes and/or a close or positive margin who did not receive post-mastectomy radiation. Local-regional recurrence rates were low in patients with negative or l-3 positive axillary nodes undergoing mastectomy without radiation. Therefore, indications for post-mastectomy radiation in patients with GMD or DM include four or more positive axillary nodes or a close or positive surgical margin. Patients with negative or l-3 positive axillary nodes should not routinely receive post-mastectomy radiation solely on the basis of the presence of GMD or DM since their risk of a local- regional recurrence is low.

The present series with more patients confirms our pre- vious report (7) that patients with GMD or DM have extensive residual disease in the breast despite excisional biopsy. Fifty-one of the 57 patients with GMD had clinical evidence of single quadrant involvement. However, pathologic examination of the mastectomy specimens revealed involvement of two or more quadrants in 23 pa-

The 5-year actuarial overall and relapse-free survival and freedom from distant metastases were not significantly different among patients with GMD or DM treated with mastectomy and patients with unifocal tumors treated with conservative surgery and radiation despite the fact that patients with GMD or DM more often had 2 four positive axillary nodes. A partial explanation for this finding may be related to the fact that patients with DM frequency had an invasive ductal carcinoma with an associated intraductal component. A decreased risk of recurrence has been reported in these patients treated either by mastectomy (23, 25) or conservative surgery and radiation (20). Fisher et al. (4) reported a significant im- provement in survival in a univariate analysis of node negative patients with an invasive ductal carcinoma and an intraductal component. Kurtz et al. (I 2) also observed

Stage I-II breast cancer 0 B. FOWBLE el al. 573

no significant differences in the lo-year survival of patients with GMD when compared to those with unifocal disease. Both groups were treated with conservative surgery and radiation.

Patterns with GMD or DM did not have an increased incidence of contralateral breast cancer. Kurtz et al. (12) reported similar findings. There also appears to be no increased incidence of contralateral breast cancer in patients with microscopic multicentric disease (28).

In summary, patients with GMD or DM treated with

mastectomy and post-operative radiotherapy where ap- propriate do not have an increased risk of local-regional recurrence unlike patients with GMD treated with conservative surgery and radiation. Indications for post-mastectomy radiation include close or positive surgical margins or four or more positive axillary nodes. Overall and relapse-free survival, freedom from distant metastases, and the incidence of a contralateral breast cancer are similar to a group of unifocal tumors treated with conservative surgery and radiation.

REFERENCES

1. American Joint Committee on Cancer. Manual for staging of cancer, 2nd edition. Philadelphia, PA: Lippincott Co.; 1983:127-134.

2. Egan, R. L. Multicentric Breast Carcinomas: Clinical-ra- diographic-pathologic whole organ studies and 10 year survival. Cancer 49: 1123- 1130; 1982.

3. Fisher, E. R.; Gregorio, R.; Redmond, C.; Vellios, F.; Som- mers, S. C.; Fisher, B. Pathologic findings from the National Surgical Adjuvant Breast Project (protocol no. 4) I. Obser- vations concerning the multicentricity of mammary cancer. Cancer 35:247-254;1975.

4. Fisher, E. R.; Redmond, C.; Fisher, B.; Bass, G. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Projects (NSABP): Prognostic discriminants for 8 year survival for node-negative invasive breast cancer patients. Cancer 65:2121-2128;1990.

5. Fourquet, A.; Campana, F.; Zafrani, B.; Mosseri, V.; Viehl, P.; Durand, J. C.; Vilcoq, J. R. Prognostic factors in the conservative management of early breast cancer: A 25 year follow-up at the Institut Curie. Int. J. Radiat. Oncol. Biol. Phys. 17:7199-7205;1989.

6. Fowble, B. Radiotherapcutic considerations in the treatment of primary breast cancer. JNCI Monog. 11:49-58; 1992.

7. Fowble, B.; Solin, L. J.; Schultz, D. J. Conservative surgery and radiation for early breast cancer. In: Fowble, B., Good- man, R. L., Click, J. H., Rosato, E. F., eds. Breast cancer treatment. A comprehensive guide to management. Phila- delphia, PA: Mosby Year Book 1991:105-149.

8. Gallagher, H. S.; Martin, J. E. The study of mammary carcinoma by mammography and whole organ sectioning. Cancer 23:855-873;1969.

9. Healy, E. A.; Osteen, R. T.; Schnitt, S. J.; Gelman, R.; Stomper, P. C.; Connolly, J. R.; Harris, J. R. Can the initial clinical and mammographic features predict the presence of an extensive intraductal component in early stage breast cancer? Int. J. Radiat. Oncol. Biol. Phys. 17:1217- 1222;1989.

10. Holland, R.; Veling, S. H. J.; Mravunac, M.; Hendriks, J. H. C. L. Histologic multifocality of Tis, T l-2 breast carcinomas. Implications for clinical trials of breast conserving surgery. Cancer 56:979-990; 1985.

1 1. Kaplan, E. L.; Meier, P. Non parametric estimation from incomplete observations. J. Am, Stat. Assoc. 53:457- 481;1958.

12. Kurtz, J. M.; Jacquemier, J.; Amahic, R.; Brandone, H.; Ayme, Y.; Hans, D.; Bressac, C.; Spitalier, J.-M. Breast conserving therapy for macroscopically multiple cancers. Ann. Surg. 2 12:38-44; 1990.

13. Kurtz, J. M.; Jacquemier, J.; Amalric, R.; Brandone, H.; Ayme, Y.; Hans, D.; Bressac, C.; Spitalier, J. Why are local recurrences after breast conserving therapy more frequent in young patients? J. Clin. Oncol. 8:59 l-598; 1990.

14. Lagios, M. D. Multicentricity of breast carcinoma demonstrated by routine correlated serial subgross and radio- graphic examination. Cancer 40: 1726-1734; 1977.

15. Lagios, M. D.; Westdahl, R. R.; Rose, M. R. The concept and implications of multicentricity in breast carcinoma. Pathol. Ann. 16(2):83-102;1981.

16. Leopold, K. A.; Recht, A.; Schnitt, S. J.; Connolly, J. L.; Rose, M. A.; Silver, B.; Harris, J. R. Results of conservative surgery and radiation therapy for multiple synchronous cancers of one breast. Int. J. Radiat. Oncol. Biol. Phys. 16: 1 I-16;1989.

17. Lesser, M. L.; Rosen, P. P.; Kinne, D. W. Multicentricity and bilaterality in invasive breast carcinoma. Surgery 9 1: 234-240; 1982.

18. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Che- mother. Rep. 50:163-170;1966.

19. Morgenstern, L.; Kaufman, P. A.; Friedman, N. B. The case against tylectomy for carcinoma ofthe breast. The factor of multicentricity. Am. J. Surg. 130:251-255;1975.

20. Osteen, R. T.; Connolly, J. L.; Recht, A.; Silver, B.; Schnitt, S. J.; Harris, J. R. Identification of patients at high risk for local recurrence after conservative surgery and radiation therapy for stage I or II breast cancer. Arch. Surg. 122: 1248- 1252;1987.

21. Recht, A.; Connolly, J. L.; Schnitt, S. J.; Silver, B.; Rose, M. A.; Love, S.; Harris, J. R. The effect of young age on tumor recurrence in the treated breast after conservative surgery and radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 14:3-10;1988.

22. Recht, A.; Harris, J. R. Selection of patients with early-stage breast cancer for conservative surgery and radiation. On- cology 4:23-32; 1990.

23. Rosen, P. P.; Kinne, D. W.; Lesser, M.; Hellman, S. Are prognostic factors for local control of breast cancer treated by primary radiotherapy significant for patients treated by mastectomy? Cancer 57: 1415-1420;1986.

24. Sarnelli, R.; Squartini, F. Multicentricity in breast cancer: A submacroscopic study. Pathol. Annu. 2 I( 1): 143- 158;1986.

25. Silverberg, S. G.; Chitale, A. R. Assessment of significance of proportions of intraductal and infiltrating tumor growth in ductal carcinoma of the breast. Cancer 32:830-837;1973.

26. Skjorten, F.; Amlie, E.; Larsen, K. A. On the occurrence of focal, occult in situ and invasive carcinoma in 250 mastectomy specimens. Eur. J. Surg. Oncol. 12: 117- 12 1; 1986.

27. Spinelli, C.; Berti, P.; Ricci, E.; Miccoli, P. Multicentric breast tumor: An anatomical-clinical study of 100 cases. Eur. J. Surg. Oncol. 18:23-26;1992.

28. Westman-Naeser, S.; Bengtsson, E.; Eriksson, 0.; Jarkrans, T.; Nordin, B.; Stenkvist, B. Multifocal breast carcinoma. Am. J. Surg. 142:255-257;1981.

the role of mastectomy in patients with stage i-ii breast cancer presenting with gross multifocal or...

Documents