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0 Clinical Original Contribution BREAST RECURRENCE AND SURVIVAL RELATED TO PRIMARY TUMOR LOCATION IN PATIENTS UNDERGOING CONSERVATIVE SURGERY AND RADIATION FOR EARLY-STAGE BREAST CANCER BARBARA FOWBLE, M.D.,’ LAWRENCE J. SOLIN, M.D.,’ DELRAY J. SCHULTZ, M.A.* AND MARISA C. WEISS, M.D.’ ‘Department of Radiation Oncology, University of Pennsylvania School of Medicine and the Fox Chase Cancer Center; and ‘Department of Statistics, University of Pennsylvania Cancer Center, Philadelphia, PA Between1977 and 1986,886 pts with Stage I and II breastcancerunderwentexcisionalbiopsy, axillarydissection and radiation.Median follow-up was 5 years (range 2 months-13 years). The patients were divided into four groups according to the primary tumor location: 1) outer (495 patients), 2) inner (202 patients), 3) central (119 patients), and 4) subareolar (70 patients). Subareolar tumors were defined as those immediately beneath the nipple-areolar complex or within 2 cm of the areolar margin. The comparability of the groups was assed in terms of clinical T stage, patient age, histology, final pathologic margin status, estrogen and progesterone receptor status, pathologic nodal status, and use of adjuvant chemotherapy. There were no significant differences among the four groups in the distribution of these factors except for the pathologic nodal status (outer 38% positive nodes, inner 24%, central 238, subareolar 31%) p = .0004. There were no significantdifferencesin 5 year actuarialoverallsurvival(91%vs 86%vs 92%vs 91%,p = .34), relapse-free(75%vs 74%vs 80%vs 79%,p = .77), or NED survival (82% vs 78% vs 87% vs 84%, p = .29) for the four groups. A separate analysis for pathologic node negative and node positive patients revealed similar findings. For node-negative patients, the 5 year actuarial overall survival was 93% vs 88% vs 94% vs 91% (p = .20), the relapse-free survival was 78% vs 76% vs 82% vs 79% (p = .49), and the NED survival was 86% vs 81% vs 88% vs 86% (p = .46). For node-positive patients, the 5 year actuarial overall survival was 87% vs 82% vs 84% vs 90% (p = .59), relapse-free survival was 69% vs 66% vs 77% vs 80% (p = .78), and NED survival was 75% vs 68% vs 85% vs 80% (p = .66). Patterns of first failure were also not significantly different among the four groups: local only first failure (7% vs 4% vs 5% vs 8%, p = .49), any load first failure, i.e., *simultaneous distant metastases (8% vs 5% vs 5% vs 9%, p = .61), regional only (2% vs 1% vs 1% vs OW, p = .65), any regional (4% vs 3% vs 3% vs 3%), or distant metastases (11% vs 17% vs 9% vs lo%, p = .16). A separate analysis of node negative and node positive patients revealed similar findings. The present analysis demonstrates no significant correlation between primary tumor location and patterns of first failure, overall survival, relapse-free, or no evidence of disease (NED) survival in 886 pts with Stage I and II breast cancer treated with conservative surgery and radiation. Subareolar tumor location was not associated with an increased risk of breast recurrence in appropriately selected patients. Breast cancer, Conservative surgery and radiation, Tumor location.
INTRODUCTION
tumors in this location may not infrequently have subclinical involvement of the nipple-areolar complex (18, 2 1, 28, 32). However, there are minimal data correlating breast recurrence following conservative surgery and radiation with primary tumor location, especially for subareolar tumors. In addition, the effect of tumor location on breast cancer survival is controversial. Several series (3, 10, 15, 22, 29) have suggested that medial lesions, especially those with negative nodes have a worse prognosis when compared to lateral tumors. The purpose of this report is to examine the influence of primary tumor
Conservative surgery and radiation represents an alternative equal to mastectomy in selected patients with early stage breast cancer (23). A number of factors related to the primary tumor have been evaluated for their impact on patient selection and include tumor size and location, the presence of gross multicentric or multifocal disease, diffuse microcalcifications, histology, and the status of resection margins (13, 24). Careful evaluation of patients with subareolar sumors has been advised (8, 24) since
This paper was presented at ASTRO, November 1991. Reprint requests to: Barbara Fowble, Dept. of Radiation Oncology, Hosp. University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104.
Accepted for publication 20 February 1992.
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location on breast recurrence and survival (overall, relapse-free, and no evidence of disease) in a group of conservatively treated patients at the University of Pennsylvania and Fox Chase Cancer Center. METHODS
AND MATERIALS
Between 1977 and 1986,886 women with AJC clinical Stage I and II (1) breast cancer underwent excisional biopsy, a level I-II axillary node dissection, and definitive irradiation at the University of Pennsylvania and Fox Chase Cancer Center. The median follow-up was 5 years with a range of 2 months to 13 years. The median age of the patient population was 5 1 years with a range of 22 to 85 years. Five hundred and nineteen patients had clinical Tl tumors and 367 had clinical T2 tumors. All patients underwent an excisional biopsy which most commonly was a wide excision with removal of a rim of normal adjacent breast tissue. Resection of the nippleareolar complex was performed in three patients. In one patient this occurred in conjunction with a quadrantectomy for an upper outer quadrant tumor and in two patients it was performed for subareolar tumors. Reexcision was performed in 437 patients and in 249 patients this revealed residual tumor. One hundred eighty eight patients had a negative reexcision. Inking of the surgical specimen with microscopic determination of the final margin was performed in 498 patients. Three hundred eighty patients had negative margins of resection, that is, > 2 mm, 43 had close margins of resection, that is, I 2 mm, and 75 patients had positive margins of resection with tumor at the resection margin. The final status of the resection margin was unknown in 388 patients (44%). All patients underwent a level I-II axillary node dissection. The median number of nodes removed was 15 with a range of l-75. Six hundred and three patients had histologically negative axillary nodes and 283 had positive axillary nodes. Two hundred and fourteen patients had one to three positive nodes, and 69 patients had four or more positive nodes. In general, radiotherapy consisted of treatment to the entire breast with tangential fields. A total dose of 4600 to 5000 cGy was delivered in 180 to 200 cGy fractions over a period of 4f to 5 weeks. The regional nodes (supraclavicular + dapical axillary) received 4600 to 5000 cGy delivered over a period of 4f to 5 weeks. A 6 MV linear accelerator was used. The primary site was boosted with either electrons, external beam radiotherapy, or an Iridium 192 implant for an additional dose of 1400 to 2000 cGy. Of the 603 patients with negative axillary nodes, 564 received treatment to the breast only, and 39 patients were treated to the breast and regional nodes. Four hundred and fifty six patients had a boost with electrons, 123 patients had a boost with an implant, 14 patients had boost treatment delivered with further external beam therapy, and 10 patients had no boost. Of the 283 patients with positive axillary nodes, 244 received treatment to
Volume 23, Number 5, I992
the breast and regional nodes, and 39 received treatment to the breast only. Two hundred and thirteen of these patients received boost treatment with electrons, 50 with an implant, and 18 with external beam therapy. Two patients received no boost. Chemotherapy consisted of cyclophosphamide, 100 mg/m2 po days 1 through 14, methotrexate, 40 mg/m* IV days 1 and 8,5_fluorouracil, 600 mg/m* IV days 1 and 8 (CMF) with or without prednisone, 40 mg/m2 days 1 through 14, of a 28 day cycle for a total of six to eight cycles. Two hundred thirty-nine patients received adjuvant systemic chemotherapy and in 228 it consisted of CMF with or without prednisone. Eleven patients received cyclophosphamide, 100 mg/m2 po days 1 through 14, doxorubicin, 30 mg/m* IV days 1 and 8, 5-fluorouracil, 500 mg/m2 IV days 1 and 8 (CAF). Of the 239 patients receiving adjuvant systemic chemotherapy, 2 14 had histologically positive axillary nodes and 25 had negative axillary nodes. Seventy-two patients received tamoxifen. In 33 patients tamoxifen was given with chemotherapy and in 39 patients tamoxifen was given alone. The patients were divided into four groups based on primary tumor location. Primary tumor location was determined by a review of the physical findings, mammographic presentation, operative reports, and photographs of the boost volume. Subareolar tumors were defined as those immediately beneath the nipple areolar complex, or within 2 cm of the areolar margin. A 2 cm margin was chosen since it has been demonstrated that tumors within this zone involve the nipple areolar complex in up to 50% of patients (18, 2 1, 28, 32). Central tumors were defined as those at 6 or 12 o’clock, > 2 cm from the areolar margin. Four hundred ninety-five patients had outer quadrant tumors, 202 had inner quadrant tumors, 119 had central tumors, and 70 patients had subareolar tumors. The comparability of the four groups were assessed in terms of clinical factors (tumor size and patient age), histopathologic factors (histologic subtype, final resection margin, estrogen and progesterone receptor status, and pathologic nodal status), and treatment related factors (the use of adjuvant systemic chemotherapy). Results are presented in terms of breast recurrence, overall, no evidence of disease (NED), and relapse-free survival (RFS). An isolated breast recurrence was defined as first site failure in the treated breast without associated simultaneous clinically apparent, regional node involvement, or distant metastasis. The overall breast recurrence rate was defined as first site of recurrence within the treated breast with or without simultaneous regional node involvement or 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 continously without evidence of disease. Patients who relapsed and subsequently underwent salvage therapy and were alive without evidence of disease were considered a failure for relapse-free survival but not NED survival.
Outcome related to primary tumor location 0
935
B. FOWBLE et al.
Table 1. Comparability of groups based on tumor location
Clinical tumor size Tl T2 Patient age I 35 36-50 2 51 Estrogen receptor Positive Negative Unknown Progesterone receptor Positive Negative Unknown Histology Ductal Lobular Other Final resection Negative Positive Close Unknown Nodal status Path NO Path N 1 l-3 24 Chemotherapy No Yes
Subareolar
Central
Inner
Outer
P
No.
(%)
No.
(%)
No.
(%)
No.
(%)
283 212
(57)
117 85
(58)
70 49
(59)
49 21
(70)
.24
43 191 261
(9)
22 72 108
(11)
10 48 61
7 28 35
(10)
.95
254 102 139
(51)
91 43 68
(45)
63 25 31
(53)
35 14 21
(50)
.92
196 112 187
(39)
69 50 83
(34)
46 29 44
(39)
22 19 29
(31)
.49
430 28 37
(87)
185 5 12
(92)
100 6 13
(84)
63 4 3
(90)
.30
221 37 23 214
(45) (7) (5) (43)
77 22 11 92
(38) (11) (5) (46)
52 10 6 51
(44) (8) (5) (43)
30 6 3 31
(43) (9) (4) (44)
.92
309 186 138 48
(62) (38)
154 48 36 12
(76) (24)
92 27 21 6
(77) (23)
48 22 19 3
(69) (31)
.003
(8)
value
margin
351 144
148 54
(29)
96 23
(27)
Survival curves and actuarial rates of breast recurrence were calculated using the Kaplan-Mair Method ( 17) with the time period beginning at the onset of definitive radiotherapy. Statistical comparisons between curves were performed using the Mantle-Cox test (20).
(19)
52 18
.19
(26)
terms of clinical tumor size, patient age, estrogen and progesterone receptor status, histology of the primary, final resection margin, or the use of adjuvant systemic chemotherapy. The only significant difference among the groups was a higher percentage of histologically positive axillary nodes in outer quadrant tumors. The 5-year actuarial risk of a breast recurrence as first site of failure related to primary tumor location is presented in Table 2. There were no statistically significant differences in the actuarial risk of a breast-only failure as related to primary tumor location for all patients, histo-
RESULTS The comparability of the four groups based on primary tumor location is presented in Table 1. There were no statistically significant differences among the groups in
Table 2. Breast recurrence as first site of failure related to primary tumor location 5-year act. % Breast only All pts. Outer Inner Central Subareolar p value
7 4 5 8 .49
Breast ? DM
Path NO
Path N 1
8 5 4 10
6 0 6 0
8 5 5 9
.24
.61
.75
All pts.
Path NO 8 5 4 12 .57
Path Nl 7 5 5 0 .60
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Volume 23, Number 5, 1992
Table 3. Regional node recurrence as first site of failure related to primary tumor location 5-vear act. % Regional only
Regional f DM
All pts.
Path NO
Path Nl
All pts.
Path NO
Path N 1
2 1 1 0 .65
1 3 0 0 .38
5 0 4 0 53
4 3 3 3 .99
2 4 1 4 .43
8 0 8 0 .25
Outer Inner Central Subareolar p value
logically node negative patients, or histologically nodepositive patients. Similarly, the 5-year actuarial overall risk of a breast failure was unrelated to primary tumor location for all patients, histologically node negative patients, or histologically node positive patients. A total of 75 patients developed a breast recurrence as the first site of failure. Forty-four patients had outer quadrant tumors, 11 inner quadrant tumors, 14 central tumors, and six subareolar. Of the 44 outer quadrant tumors that recurred, 32 were true or marginal (in the vicinity of the primary) in location, and 12 were elsewhere (quadrant separate from the original primary). Of the 11 inner quadrant recurrences, eight were true or marginal and three elsewhere. Eleven of the central tumor recurrences were true or marginal and two were elsewhere. One was diffuse. Four of the subareolar recurrences were true or marginal and two were elsewhere. Regional node recurrence as first side of failure related to primary tumor location is presented in Table 3. There were no statistically significant differences among the four groups in regional only failure or overall regional failure for all patients, pathologically node-negative, or pathologically node-positive patients. The 5-year actuarial risk of distant metastasis is presented in Table 4. Among the four groups, there is no statistically significant difference in the 5-year actuarial risk of distant metastases for all patients, pathologic negative patients, or pathologic node-positive patients. Five-year actuarial survival results are presented in Table 5. There were no statistically significant differences among the four groups in terms of overall, NED, or relapse-free survival for all patients, pathologic node-neg-
Table 4. Distant metastases (DM) related to primary tumor location 5-year act. % DM
Outer Inner Central Subareolar p value
All pts.
Path NO
Path N 1
11 17 9 10 .I6
10 15 9 6
14 25 12 20 .64
.17
ative, or pathologic node-positive patients. The 5-year actuarial overall survival for outer quadrant tumors was 91%, for inner quadrant 86%, for central 92%, and for subareolar tumors 9 1%. For pathologic node negative patients, the 5-year actuarial overall survival was 93% for outer tumors, 88% for inner, 94% for central, and 9 1% for subareolar tumors. For pathologic node positive patients, the 5-year overall survival was 87% for outer, 82% for inner, 84% for central, and 90% for subareolar tumors. A separate analysis was performed for patients receiving chemotherapy, since in a previous report (14) a statistically significant decrease in the 5-year actuarial risk of a breast-only recurrence was noted with the addition of adjuvant systemic chemotherapy (Tables 6 and 7). For patients receiving adjuvant chemotherapy, there were no significant differences among the four groups in the 5year actuarial risk of a breast or regional recurrence or distant metastases. There were also no significant differences for overall survival, NED, or relapse-free survival among the four groups. For patients not receiving adjuvant chemotherapy, there were no significant differences among the four groups in terms of the 5-year actuarial risk of a breast or regional node recurrence. Of borderline significance (p = .05) was the 5-year actuarial risk of distant metastases with inner quadrant tumors having the highest risk. There were no significant differences among the four groups in terms of overall survival, NED, or relapse-free survival. DISCUSSION
In this study, the distribution of the 886 Stage I-II breast cancers by primary tumor location was 56% outer quadrant tumors, 23% inner, 13% central, and 8% subareolar. Similar distributions have been reported by other authors. Haagensen ( 16) noted 50% of 9 17 Stage A and B cancers to be outer quadrant in location, 23% inner, and 27% central. Subareolar tumors represented a subset of central tumors and were defined as those occurring with 1 cm of the areolar margin. Donegan (9), in a series of 2045 breast cancers representing all stages, reported 45% outer quadrant tumors, 17% inner, 3% central, and 15% subareolar. Twenty percent were diffuse. Fisher et al. (11) reported that 67% of 1392 operable breast cancers were located in
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Outcome related to primary tumor location 0 B. FOWBLE ef al.
Table 5. Survival related to primary tumor location 5-vear act. % Overall
Outer Inner Central Subareolar p value
All pts.
Path NO
Path N 1
All pts.
Path NO
Path Nl
All pts.
Path NO
Path Nl
91 86 92 91 .34
93 88 94 91 .20
87 82 84 90 .59
82 78 87 84 .29
86 81 88 86 .46
75 68 85 80 .66
75 74 80 79 .77
78 76 82 79 .49
69 66 77 80 .78
the outer quadrants, 27% inner, 6.5% central, and 4.7% subareolar. Sixty percent of 7 11 operable breast cancers reported by Veronesi and Valagussa (3 1) were outer quadrant, 2 1% inner and 19% central. Nemoto el al. (22), in an update of the 1978 National Survey of the American College of Surgeons, reported 74% of 9401 women with breast cancer to have outer quadrant tumors and 26% had central or inner quadrant tumors. The current analysis demonstrated no significant differences among the four groups based on tumor location in terms of clinical tumor size, patient age, histology, receptor status, final resection margin, or the use of adjuvant systemic chemotherapy. There was, however, a statistically significant difference in pathologic nodal status with outer quadrant tumors having a higher incidence of histologically positive axillary nodes (38% outer quadrant, 24% inner, 23% central, 3 1% subareolar). Others have also noted a greater propensity for positive axillary nodes in outer quadrant tumors although the differences have not been statistically significant. (11, 16, 22, 3 1). Fisher et al. (1 l), in a series of 540 women treated with radical mastectomy on the NSABP B-04 protocol, reported 52% of outer quadrant tumors to have positive axillary nodes compared to 46% for medial lesions, 54% for central, 47% for medial-central, and 54% for subareolar. Veronesi and Valagussa (3 1) reported 56% axillary node positivity for lateral tumors compared to 47% for medial tumors in patients undergoing radical mastectomy. In the National Survey by the American College of Surgeons (22), 43% of lateral tumors had positive axillary nodes compared to
Table 6. 5-year actuarial results related to primary tumor location in patients receiving adjuvant chemotherapy
Breast only Breast + DM Regional only Regional f DM Distant mets Survival OS NED RFS
Relapse-free
NED
Outer
Inner
Central
Subareolar
p value
4 6 6 8 15
0 4 0 0 14
0 0 0 9 15
0 0 0 0 17
.32 .49 .44 .18 .98
88 74 70
86 78 78
81 82 78
94 83 83
.77 .92 .67
34% for medial tumors. The survey also demonstrated no significant differences in primary tumor size for lateral or medial lesions. The present series revealed no significant differences in the 5-year actuarial risk of breast recurrence based on primary tumor location. In particular, subareolar tumors did not have an increased risk of breast recurrence. Only two of these patients had resection of the nipple-areolar complex. Several histopathologic studies have demonstrated that tumors within 2-2.5 cm of the areolar margin involve the nipple areolar complex in up to 40-50% of cases (18, 2 1, 28). The incidence of involvement of this structure is greater for T2 tumors when compared to Tl ( 18, 2 1, 28) and for patients with positive axillary nodes (18, 28, 32). The most common mechanism for involvement is direct intraductal extension (2 1,28). Other mechanisms include stromal invasion, lymphatic extension, or
Table 7. 5-year actuarial results related to primary tumor location in patients not receiving adjuvant chemotherapy Outer Breast only Breast + DM Regional only Regional If: DM Distant mets Survival OS NED RFS
9 9 1 2 10 92 85 77
Inner 5
Central
Subareolar
p value
: 4 18
5 5 0 1 8
10 12 0 4 7
.66 .56 .31 .44 .05
87 78 73
95 88 81
89 85 79
.26 .22 .75
Table 8. Breast recurrence following conservative surgery and radiation related to location of primary tumor % Breast recurrence Central/innter Calle et al. (6) Balawadjer et al. (2) Van Limbergen et. al. (30) Chauvet et al. (7) Boyages et al. (5) Present series
Outer
9 14 9
7 10 9
14
11
919 514
11 7
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Volume 23, Number
Table 9. Survival related to primary
5, I992
tumor location
S-vear act. survival (DFS) Outer
All pts. Present series Veronesi and Valagussa (3 1) Fisher et al. ( 11) Node negative Present series Veronesi and Valagussa (3 1) Fisher et al. ( 11) Nemoto et al. (22) Node positive Present series Veronesi and Valagussa (3 1) Fisher et al. (11) Nemoto et al. (22) * All medial tumors
including
Inner
Central
Subareolar
Overall survival
Disease free survival
Overall survival
Disease free survival
Overall survival
Disease free survival
Overall survival
Disease free survival
91 77 71
(82)
86
(78)
92 70 72*
(87) (61)*
91
(84)
(58)
88
(81)
94 82 82*
(88)
91
(86)
(78)*
90
(80)
93 94 86
(86) (84) (67)
87 63 58
(63)* 82
(75) (39)
(68)
84 58 60*
(85) (42)* (39)*
(42) inner, central, and subareolar.
a separate independent focus (21, 28). A subareolar location has also been associated with an increased risk of multicentricity (12, 26). Rosen et al. (26) reported 80% of subareolar lesions to demonstrate multicentric foci of cancer compared to 25-35% of noncentral lesions. Nipple involvement was noted in 38% of patients with multicentricity by Luttges et al. (19). In a series of eight patients with subareolar tumors who underwent mastectomy at the University of Pennsylvania, four were found to have extensive residual tumor in the breast (8). Theoretically these factors may contribute to an increased risk of breast recurrence in patients undergoing conservative surgery and radiation. Three series have suggested an increased risk of breast recurrence in patients with ductal carcinoma in situ treated with conservative surgery and radiation in whom the primary tumor was central in location or associated with a bloody nipple discharge (4,25,27). Breast recurrence related to primary tumor location for patients with Stages I-II invasive breast cancer are presented in Table 8. A central or inner quadrant location is not associated with an increased risk of breast recurrence. In the present series, subareolar tumors also did not have a greater risk for breast recurrence. Since adjuvant chemotherapy in conjunction with breast irradiation has been associated with a decreased risk of breast recurrence (14), a separate analysis was performed for this group of patients. Again there was no significant association between primary tumor location and the risk of a breast recurrence. Similar findings were observed for patients who did not
receive chemotherapy. The location of the recurrence within the treated breast was also similar for each of the four primary tumor locations. Although, subareolar tumors did have a slightly higher incidence of elsewhere recurrences. This observation may in part reflect the greater likelihood of multicentricity for subareolar tumors. However, the patient numbers are too small to draw definitive conclusions. Survival and disease-free survival related to primary tumor location are presented in Table 9. The only study that has demonstrated a statistically significant difference in survival is the National Survey by the American College of Surgeons (22). The significant difference, however, was limited to node-negative patients who underwent mastectomy without postoperative radiotherapy. No significant differences in overall survival, relapse-free, or NED survival were found in the present study for all patients, node-negative or node-positive. Patients with inner quadrant tumors who did not receive chemotherapy had an increased risk of distant metastases (p = .05), however, this did not translate into a significant decrease in survival. In summary, the present analysis demonstrates no significant correlation between primary tumor location and patterns of first failure, overall survival, relapse-free, or NED survival in 886 patients with Stage I and II breast cancer treated with conservative surgery and radiation. Subareolar tumor location was not associated with an increased risk of breast recurrence in appropriately selected patients, i.e., those with limited tumor extent.
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Outcome related to primary tumor location 0 B. FOWBLE etal.
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18.
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incomplete observations. J. Am. Stat. Assoc. 53:457481;1958. Lagios, M. D.; Gates, E. A.; Westdahl, P. R.; Richards, V.; Alpert, B. S. A guide to the frequency of nipple involvement in breast cancer. A study of 149 consecutive mastectomies using a serial subgross and correlated radiographic technique. Am. J. Surgery 138:135-142;1989. Luttges, J.; Kalbfleisch, H.; Prinz, P. Nipple involvement and multicentricity in breast cancer. A study on whole organ sections. Cancer Res. Clin. Oncol. 113:48 l-487; 1987. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 50: 163- 170; 1966. Morimoto, T.; Komaki, K.; Kozo, I.; Umemoto, A.; Yamamoto, H.; Harada, K.; Inoue, K. Involvement of the nipple and areola in early breast cancer. Cancer 55:24592463;1985. Nemoto, T.; Natarajan, N.; Bedwani, R.; Vana, J.; Murphy, G. P. Breast cancer in the medial half: results of the 1978 national survey of the American College of Surgeons. Cancer 51:133-1338;1983. NIH Consensus Conference: Treatment of early-stage breast cancer. JAMA 265:39 1;1991. Recht, A. and Harris, J. R. Selection of patients with earlystage breast cancer for conservative surgery and radiation. Oncology 4:23-30; 199 1. Recht, A.; Danoff, B. F.; Solin, L. J.; Schnitt, S.; Connolly, J.; Botnick, L.; Goldberg, I.; Goodman, R. L.; Harris, J. R. Intraductal carcinoma of the breast: Results of treatment with excisional biopsy and irradiation. J. Clin. Oncol 3: 1339-1343;1985. Rosen, P. P.; Fracchia, A. A.; Urban, J. A.; Schottenfield, D.; Robbins, G. Residual mammary carcinoma following simulated partial mastectomy. Cancer 35:739-747;1975. Solin, L. J.; Fowble, B. L.; Schultz, D. J.; Yeh, I-Tien; Kowalyshyn, M. J.; Goodman, R. L. Definitive irradiation for intraductal carcinoma of the breast. Int. J. Radiat. Oncol. Biol. Phys. 19:843-850;1990. Suehiro, S.; Inai, K.; Tokuoka, S.; Hamada, Y.; Toi, M.; Niimoto, M.; Hattori, T. Involvement of the nipple in early carcinoma of the breast. Surg. Gynecol. Obstet. 168:244248;1989. Urban, J. A. Clinical experience and results of excision of the internal mammary lymph node chain in primary operable breast cancer. Cancer 12: 14; 1959. Van Limbergen, E.; Van der Bogaert, W.; Van der Schueren, E.; Rijnders, A. Tumor excision and radiotherapy as primary treatment of breast cancer. Analysis of patient and treatment parameters and local control. Radiother. Oncol. 8: 1-9; 1987. Veronesi, U. and Valagussa, P. Inefficacy of internal mammary nodes dissection in breast cancer surgery. Cancer 47: 170-175;1981. Wertheim, U. and Ozzello, L. Neoplastic involvement of the nipple and skin flap in carcinoma of the breast. Am. J. Surg. Path. 4543-549; 1980.
Copyngh:
0360.3016192 $5.00 + .I0 0 1992 Pergamon Press Ltd.
0 Clinical Original Contribution BREAST RECURRENCE AND SURVIVAL RELATED TO PRIMARY TUMOR LOCATION IN PATIENTS UNDERGOING CONSERVATIVE SURGERY AND RADIATION FOR EARLY-STAGE BREAST CANCER BARBARA FOWBLE, M.D.,’ LAWRENCE J. SOLIN, M.D.,’ DELRAY J. SCHULTZ, M.A.* AND MARISA C. WEISS, M.D.’ ‘Department of Radiation Oncology, University of Pennsylvania School of Medicine and the Fox Chase Cancer Center; and ‘Department of Statistics, University of Pennsylvania Cancer Center, Philadelphia, PA Between1977 and 1986,886 pts with Stage I and II breastcancerunderwentexcisionalbiopsy, axillarydissection and radiation.Median follow-up was 5 years (range 2 months-13 years). The patients were divided into four groups according to the primary tumor location: 1) outer (495 patients), 2) inner (202 patients), 3) central (119 patients), and 4) subareolar (70 patients). Subareolar tumors were defined as those immediately beneath the nipple-areolar complex or within 2 cm of the areolar margin. The comparability of the groups was assed in terms of clinical T stage, patient age, histology, final pathologic margin status, estrogen and progesterone receptor status, pathologic nodal status, and use of adjuvant chemotherapy. There were no significant differences among the four groups in the distribution of these factors except for the pathologic nodal status (outer 38% positive nodes, inner 24%, central 238, subareolar 31%) p = .0004. There were no significantdifferencesin 5 year actuarialoverallsurvival(91%vs 86%vs 92%vs 91%,p = .34), relapse-free(75%vs 74%vs 80%vs 79%,p = .77), or NED survival (82% vs 78% vs 87% vs 84%, p = .29) for the four groups. A separate analysis for pathologic node negative and node positive patients revealed similar findings. For node-negative patients, the 5 year actuarial overall survival was 93% vs 88% vs 94% vs 91% (p = .20), the relapse-free survival was 78% vs 76% vs 82% vs 79% (p = .49), and the NED survival was 86% vs 81% vs 88% vs 86% (p = .46). For node-positive patients, the 5 year actuarial overall survival was 87% vs 82% vs 84% vs 90% (p = .59), relapse-free survival was 69% vs 66% vs 77% vs 80% (p = .78), and NED survival was 75% vs 68% vs 85% vs 80% (p = .66). Patterns of first failure were also not significantly different among the four groups: local only first failure (7% vs 4% vs 5% vs 8%, p = .49), any load first failure, i.e., *simultaneous distant metastases (8% vs 5% vs 5% vs 9%, p = .61), regional only (2% vs 1% vs 1% vs OW, p = .65), any regional (4% vs 3% vs 3% vs 3%), or distant metastases (11% vs 17% vs 9% vs lo%, p = .16). A separate analysis of node negative and node positive patients revealed similar findings. The present analysis demonstrates no significant correlation between primary tumor location and patterns of first failure, overall survival, relapse-free, or no evidence of disease (NED) survival in 886 pts with Stage I and II breast cancer treated with conservative surgery and radiation. Subareolar tumor location was not associated with an increased risk of breast recurrence in appropriately selected patients. Breast cancer, Conservative surgery and radiation, Tumor location.
INTRODUCTION
tumors in this location may not infrequently have subclinical involvement of the nipple-areolar complex (18, 2 1, 28, 32). However, there are minimal data correlating breast recurrence following conservative surgery and radiation with primary tumor location, especially for subareolar tumors. In addition, the effect of tumor location on breast cancer survival is controversial. Several series (3, 10, 15, 22, 29) have suggested that medial lesions, especially those with negative nodes have a worse prognosis when compared to lateral tumors. The purpose of this report is to examine the influence of primary tumor
Conservative surgery and radiation represents an alternative equal to mastectomy in selected patients with early stage breast cancer (23). A number of factors related to the primary tumor have been evaluated for their impact on patient selection and include tumor size and location, the presence of gross multicentric or multifocal disease, diffuse microcalcifications, histology, and the status of resection margins (13, 24). Careful evaluation of patients with subareolar sumors has been advised (8, 24) since
This paper was presented at ASTRO, November 1991. Reprint requests to: Barbara Fowble, Dept. of Radiation Oncology, Hosp. University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104.
Accepted for publication 20 February 1992.
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location on breast recurrence and survival (overall, relapse-free, and no evidence of disease) in a group of conservatively treated patients at the University of Pennsylvania and Fox Chase Cancer Center. METHODS
AND MATERIALS
Between 1977 and 1986,886 women with AJC clinical Stage I and II (1) breast cancer underwent excisional biopsy, a level I-II axillary node dissection, and definitive irradiation at the University of Pennsylvania and Fox Chase Cancer Center. The median follow-up was 5 years with a range of 2 months to 13 years. The median age of the patient population was 5 1 years with a range of 22 to 85 years. Five hundred and nineteen patients had clinical Tl tumors and 367 had clinical T2 tumors. All patients underwent an excisional biopsy which most commonly was a wide excision with removal of a rim of normal adjacent breast tissue. Resection of the nippleareolar complex was performed in three patients. In one patient this occurred in conjunction with a quadrantectomy for an upper outer quadrant tumor and in two patients it was performed for subareolar tumors. Reexcision was performed in 437 patients and in 249 patients this revealed residual tumor. One hundred eighty eight patients had a negative reexcision. Inking of the surgical specimen with microscopic determination of the final margin was performed in 498 patients. Three hundred eighty patients had negative margins of resection, that is, > 2 mm, 43 had close margins of resection, that is, I 2 mm, and 75 patients had positive margins of resection with tumor at the resection margin. The final status of the resection margin was unknown in 388 patients (44%). All patients underwent a level I-II axillary node dissection. The median number of nodes removed was 15 with a range of l-75. Six hundred and three patients had histologically negative axillary nodes and 283 had positive axillary nodes. Two hundred and fourteen patients had one to three positive nodes, and 69 patients had four or more positive nodes. In general, radiotherapy consisted of treatment to the entire breast with tangential fields. A total dose of 4600 to 5000 cGy was delivered in 180 to 200 cGy fractions over a period of 4f to 5 weeks. The regional nodes (supraclavicular + dapical axillary) received 4600 to 5000 cGy delivered over a period of 4f to 5 weeks. A 6 MV linear accelerator was used. The primary site was boosted with either electrons, external beam radiotherapy, or an Iridium 192 implant for an additional dose of 1400 to 2000 cGy. Of the 603 patients with negative axillary nodes, 564 received treatment to the breast only, and 39 patients were treated to the breast and regional nodes. Four hundred and fifty six patients had a boost with electrons, 123 patients had a boost with an implant, 14 patients had boost treatment delivered with further external beam therapy, and 10 patients had no boost. Of the 283 patients with positive axillary nodes, 244 received treatment to
Volume 23, Number 5, I992
the breast and regional nodes, and 39 received treatment to the breast only. Two hundred and thirteen of these patients received boost treatment with electrons, 50 with an implant, and 18 with external beam therapy. Two patients received no boost. Chemotherapy consisted of cyclophosphamide, 100 mg/m2 po days 1 through 14, methotrexate, 40 mg/m* IV days 1 and 8,5_fluorouracil, 600 mg/m* IV days 1 and 8 (CMF) with or without prednisone, 40 mg/m2 days 1 through 14, of a 28 day cycle for a total of six to eight cycles. Two hundred thirty-nine patients received adjuvant systemic chemotherapy and in 228 it consisted of CMF with or without prednisone. Eleven patients received cyclophosphamide, 100 mg/m2 po days 1 through 14, doxorubicin, 30 mg/m* IV days 1 and 8, 5-fluorouracil, 500 mg/m2 IV days 1 and 8 (CAF). Of the 239 patients receiving adjuvant systemic chemotherapy, 2 14 had histologically positive axillary nodes and 25 had negative axillary nodes. Seventy-two patients received tamoxifen. In 33 patients tamoxifen was given with chemotherapy and in 39 patients tamoxifen was given alone. The patients were divided into four groups based on primary tumor location. Primary tumor location was determined by a review of the physical findings, mammographic presentation, operative reports, and photographs of the boost volume. Subareolar tumors were defined as those immediately beneath the nipple areolar complex, or within 2 cm of the areolar margin. A 2 cm margin was chosen since it has been demonstrated that tumors within this zone involve the nipple areolar complex in up to 50% of patients (18, 2 1, 28, 32). Central tumors were defined as those at 6 or 12 o’clock, > 2 cm from the areolar margin. Four hundred ninety-five patients had outer quadrant tumors, 202 had inner quadrant tumors, 119 had central tumors, and 70 patients had subareolar tumors. The comparability of the four groups were assessed in terms of clinical factors (tumor size and patient age), histopathologic factors (histologic subtype, final resection margin, estrogen and progesterone receptor status, and pathologic nodal status), and treatment related factors (the use of adjuvant systemic chemotherapy). Results are presented in terms of breast recurrence, overall, no evidence of disease (NED), and relapse-free survival (RFS). An isolated breast recurrence was defined as first site failure in the treated breast without associated simultaneous clinically apparent, regional node involvement, or distant metastasis. The overall breast recurrence rate was defined as first site of recurrence within the treated breast with or without simultaneous regional node involvement or 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 continously without evidence of disease. Patients who relapsed and subsequently underwent salvage therapy and were alive without evidence of disease were considered a failure for relapse-free survival but not NED survival.
Outcome related to primary tumor location 0
935
B. FOWBLE et al.
Table 1. Comparability of groups based on tumor location
Clinical tumor size Tl T2 Patient age I 35 36-50 2 51 Estrogen receptor Positive Negative Unknown Progesterone receptor Positive Negative Unknown Histology Ductal Lobular Other Final resection Negative Positive Close Unknown Nodal status Path NO Path N 1 l-3 24 Chemotherapy No Yes
Subareolar
Central
Inner
Outer
P
No.
(%)
No.
(%)
No.
(%)
No.
(%)
283 212
(57)
117 85
(58)
70 49
(59)
49 21
(70)
.24
43 191 261
(9)
22 72 108
(11)
10 48 61
7 28 35
(10)
.95
254 102 139
(51)
91 43 68
(45)
63 25 31
(53)
35 14 21
(50)
.92
196 112 187
(39)
69 50 83
(34)
46 29 44
(39)
22 19 29
(31)
.49
430 28 37
(87)
185 5 12
(92)
100 6 13
(84)
63 4 3
(90)
.30
221 37 23 214
(45) (7) (5) (43)
77 22 11 92
(38) (11) (5) (46)
52 10 6 51
(44) (8) (5) (43)
30 6 3 31
(43) (9) (4) (44)
.92
309 186 138 48
(62) (38)
154 48 36 12
(76) (24)
92 27 21 6
(77) (23)
48 22 19 3
(69) (31)
.003
(8)
value
margin
351 144
148 54
(29)
96 23
(27)
Survival curves and actuarial rates of breast recurrence were calculated using the Kaplan-Mair Method ( 17) with the time period beginning at the onset of definitive radiotherapy. Statistical comparisons between curves were performed using the Mantle-Cox test (20).
(19)
52 18
.19
(26)
terms of clinical tumor size, patient age, estrogen and progesterone receptor status, histology of the primary, final resection margin, or the use of adjuvant systemic chemotherapy. The only significant difference among the groups was a higher percentage of histologically positive axillary nodes in outer quadrant tumors. The 5-year actuarial risk of a breast recurrence as first site of failure related to primary tumor location is presented in Table 2. There were no statistically significant differences in the actuarial risk of a breast-only failure as related to primary tumor location for all patients, histo-
RESULTS The comparability of the four groups based on primary tumor location is presented in Table 1. There were no statistically significant differences among the groups in
Table 2. Breast recurrence as first site of failure related to primary tumor location 5-year act. % Breast only All pts. Outer Inner Central Subareolar p value
7 4 5 8 .49
Breast ? DM
Path NO
Path N 1
8 5 4 10
6 0 6 0
8 5 5 9
.24
.61
.75
All pts.
Path NO 8 5 4 12 .57
Path Nl 7 5 5 0 .60
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Volume 23, Number 5, 1992
Table 3. Regional node recurrence as first site of failure related to primary tumor location 5-vear act. % Regional only
Regional f DM
All pts.
Path NO
Path Nl
All pts.
Path NO
Path N 1
2 1 1 0 .65
1 3 0 0 .38
5 0 4 0 53
4 3 3 3 .99
2 4 1 4 .43
8 0 8 0 .25
Outer Inner Central Subareolar p value
logically node negative patients, or histologically nodepositive patients. Similarly, the 5-year actuarial overall risk of a breast failure was unrelated to primary tumor location for all patients, histologically node negative patients, or histologically node positive patients. A total of 75 patients developed a breast recurrence as the first site of failure. Forty-four patients had outer quadrant tumors, 11 inner quadrant tumors, 14 central tumors, and six subareolar. Of the 44 outer quadrant tumors that recurred, 32 were true or marginal (in the vicinity of the primary) in location, and 12 were elsewhere (quadrant separate from the original primary). Of the 11 inner quadrant recurrences, eight were true or marginal and three elsewhere. Eleven of the central tumor recurrences were true or marginal and two were elsewhere. One was diffuse. Four of the subareolar recurrences were true or marginal and two were elsewhere. Regional node recurrence as first side of failure related to primary tumor location is presented in Table 3. There were no statistically significant differences among the four groups in regional only failure or overall regional failure for all patients, pathologically node-negative, or pathologically node-positive patients. The 5-year actuarial risk of distant metastasis is presented in Table 4. Among the four groups, there is no statistically significant difference in the 5-year actuarial risk of distant metastases for all patients, pathologic negative patients, or pathologic node-positive patients. Five-year actuarial survival results are presented in Table 5. There were no statistically significant differences among the four groups in terms of overall, NED, or relapse-free survival for all patients, pathologic node-neg-
Table 4. Distant metastases (DM) related to primary tumor location 5-year act. % DM
Outer Inner Central Subareolar p value
All pts.
Path NO
Path N 1
11 17 9 10 .I6
10 15 9 6
14 25 12 20 .64
.17
ative, or pathologic node-positive patients. The 5-year actuarial overall survival for outer quadrant tumors was 91%, for inner quadrant 86%, for central 92%, and for subareolar tumors 9 1%. For pathologic node negative patients, the 5-year actuarial overall survival was 93% for outer tumors, 88% for inner, 94% for central, and 9 1% for subareolar tumors. For pathologic node positive patients, the 5-year overall survival was 87% for outer, 82% for inner, 84% for central, and 90% for subareolar tumors. A separate analysis was performed for patients receiving chemotherapy, since in a previous report (14) a statistically significant decrease in the 5-year actuarial risk of a breast-only recurrence was noted with the addition of adjuvant systemic chemotherapy (Tables 6 and 7). For patients receiving adjuvant chemotherapy, there were no significant differences among the four groups in the 5year actuarial risk of a breast or regional recurrence or distant metastases. There were also no significant differences for overall survival, NED, or relapse-free survival among the four groups. For patients not receiving adjuvant chemotherapy, there were no significant differences among the four groups in terms of the 5-year actuarial risk of a breast or regional node recurrence. Of borderline significance (p = .05) was the 5-year actuarial risk of distant metastases with inner quadrant tumors having the highest risk. There were no significant differences among the four groups in terms of overall survival, NED, or relapse-free survival. DISCUSSION
In this study, the distribution of the 886 Stage I-II breast cancers by primary tumor location was 56% outer quadrant tumors, 23% inner, 13% central, and 8% subareolar. Similar distributions have been reported by other authors. Haagensen ( 16) noted 50% of 9 17 Stage A and B cancers to be outer quadrant in location, 23% inner, and 27% central. Subareolar tumors represented a subset of central tumors and were defined as those occurring with 1 cm of the areolar margin. Donegan (9), in a series of 2045 breast cancers representing all stages, reported 45% outer quadrant tumors, 17% inner, 3% central, and 15% subareolar. Twenty percent were diffuse. Fisher et al. (11) reported that 67% of 1392 operable breast cancers were located in
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Outcome related to primary tumor location 0 B. FOWBLE ef al.
Table 5. Survival related to primary tumor location 5-vear act. % Overall
Outer Inner Central Subareolar p value
All pts.
Path NO
Path N 1
All pts.
Path NO
Path Nl
All pts.
Path NO
Path Nl
91 86 92 91 .34
93 88 94 91 .20
87 82 84 90 .59
82 78 87 84 .29
86 81 88 86 .46
75 68 85 80 .66
75 74 80 79 .77
78 76 82 79 .49
69 66 77 80 .78
the outer quadrants, 27% inner, 6.5% central, and 4.7% subareolar. Sixty percent of 7 11 operable breast cancers reported by Veronesi and Valagussa (3 1) were outer quadrant, 2 1% inner and 19% central. Nemoto el al. (22), in an update of the 1978 National Survey of the American College of Surgeons, reported 74% of 9401 women with breast cancer to have outer quadrant tumors and 26% had central or inner quadrant tumors. The current analysis demonstrated no significant differences among the four groups based on tumor location in terms of clinical tumor size, patient age, histology, receptor status, final resection margin, or the use of adjuvant systemic chemotherapy. There was, however, a statistically significant difference in pathologic nodal status with outer quadrant tumors having a higher incidence of histologically positive axillary nodes (38% outer quadrant, 24% inner, 23% central, 3 1% subareolar). Others have also noted a greater propensity for positive axillary nodes in outer quadrant tumors although the differences have not been statistically significant. (11, 16, 22, 3 1). Fisher et al. (1 l), in a series of 540 women treated with radical mastectomy on the NSABP B-04 protocol, reported 52% of outer quadrant tumors to have positive axillary nodes compared to 46% for medial lesions, 54% for central, 47% for medial-central, and 54% for subareolar. Veronesi and Valagussa (3 1) reported 56% axillary node positivity for lateral tumors compared to 47% for medial tumors in patients undergoing radical mastectomy. In the National Survey by the American College of Surgeons (22), 43% of lateral tumors had positive axillary nodes compared to
Table 6. 5-year actuarial results related to primary tumor location in patients receiving adjuvant chemotherapy
Breast only Breast + DM Regional only Regional f DM Distant mets Survival OS NED RFS
Relapse-free
NED
Outer
Inner
Central
Subareolar
p value
4 6 6 8 15
0 4 0 0 14
0 0 0 9 15
0 0 0 0 17
.32 .49 .44 .18 .98
88 74 70
86 78 78
81 82 78
94 83 83
.77 .92 .67
34% for medial tumors. The survey also demonstrated no significant differences in primary tumor size for lateral or medial lesions. The present series revealed no significant differences in the 5-year actuarial risk of breast recurrence based on primary tumor location. In particular, subareolar tumors did not have an increased risk of breast recurrence. Only two of these patients had resection of the nipple-areolar complex. Several histopathologic studies have demonstrated that tumors within 2-2.5 cm of the areolar margin involve the nipple areolar complex in up to 40-50% of cases (18, 2 1, 28). The incidence of involvement of this structure is greater for T2 tumors when compared to Tl ( 18, 2 1, 28) and for patients with positive axillary nodes (18, 28, 32). The most common mechanism for involvement is direct intraductal extension (2 1,28). Other mechanisms include stromal invasion, lymphatic extension, or
Table 7. 5-year actuarial results related to primary tumor location in patients not receiving adjuvant chemotherapy Outer Breast only Breast + DM Regional only Regional If: DM Distant mets Survival OS NED RFS
9 9 1 2 10 92 85 77
Inner 5
Central
Subareolar
p value
: 4 18
5 5 0 1 8
10 12 0 4 7
.66 .56 .31 .44 .05
87 78 73
95 88 81
89 85 79
.26 .22 .75
Table 8. Breast recurrence following conservative surgery and radiation related to location of primary tumor % Breast recurrence Central/innter Calle et al. (6) Balawadjer et al. (2) Van Limbergen et. al. (30) Chauvet et al. (7) Boyages et al. (5) Present series
Outer
9 14 9
7 10 9
14
11
919 514
11 7
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Volume 23, Number
Table 9. Survival related to primary
5, I992
tumor location
S-vear act. survival (DFS) Outer
All pts. Present series Veronesi and Valagussa (3 1) Fisher et al. ( 11) Node negative Present series Veronesi and Valagussa (3 1) Fisher et al. ( 11) Nemoto et al. (22) Node positive Present series Veronesi and Valagussa (3 1) Fisher et al. (11) Nemoto et al. (22) * All medial tumors
including
Inner
Central
Subareolar
Overall survival
Disease free survival
Overall survival
Disease free survival
Overall survival
Disease free survival
Overall survival
Disease free survival
91 77 71
(82)
86
(78)
92 70 72*
(87) (61)*
91
(84)
(58)
88
(81)
94 82 82*
(88)
91
(86)
(78)*
90
(80)
93 94 86
(86) (84) (67)
87 63 58
(63)* 82
(75) (39)
(68)
84 58 60*
(85) (42)* (39)*
(42) inner, central, and subareolar.
a separate independent focus (21, 28). A subareolar location has also been associated with an increased risk of multicentricity (12, 26). Rosen et al. (26) reported 80% of subareolar lesions to demonstrate multicentric foci of cancer compared to 25-35% of noncentral lesions. Nipple involvement was noted in 38% of patients with multicentricity by Luttges et al. (19). In a series of eight patients with subareolar tumors who underwent mastectomy at the University of Pennsylvania, four were found to have extensive residual tumor in the breast (8). Theoretically these factors may contribute to an increased risk of breast recurrence in patients undergoing conservative surgery and radiation. Three series have suggested an increased risk of breast recurrence in patients with ductal carcinoma in situ treated with conservative surgery and radiation in whom the primary tumor was central in location or associated with a bloody nipple discharge (4,25,27). Breast recurrence related to primary tumor location for patients with Stages I-II invasive breast cancer are presented in Table 8. A central or inner quadrant location is not associated with an increased risk of breast recurrence. In the present series, subareolar tumors also did not have a greater risk for breast recurrence. Since adjuvant chemotherapy in conjunction with breast irradiation has been associated with a decreased risk of breast recurrence (14), a separate analysis was performed for this group of patients. Again there was no significant association between primary tumor location and the risk of a breast recurrence. Similar findings were observed for patients who did not
receive chemotherapy. The location of the recurrence within the treated breast was also similar for each of the four primary tumor locations. Although, subareolar tumors did have a slightly higher incidence of elsewhere recurrences. This observation may in part reflect the greater likelihood of multicentricity for subareolar tumors. However, the patient numbers are too small to draw definitive conclusions. Survival and disease-free survival related to primary tumor location are presented in Table 9. The only study that has demonstrated a statistically significant difference in survival is the National Survey by the American College of Surgeons (22). The significant difference, however, was limited to node-negative patients who underwent mastectomy without postoperative radiotherapy. No significant differences in overall survival, relapse-free, or NED survival were found in the present study for all patients, node-negative or node-positive. Patients with inner quadrant tumors who did not receive chemotherapy had an increased risk of distant metastases (p = .05), however, this did not translate into a significant decrease in survival. In summary, the present analysis demonstrates no significant correlation between primary tumor location and patterns of first failure, overall survival, relapse-free, or NED survival in 886 patients with Stage I and II breast cancer treated with conservative surgery and radiation. Subareolar tumor location was not associated with an increased risk of breast recurrence in appropriately selected patients, i.e., those with limited tumor extent.
REFERENCES 1. American Joint Committee on Cancer. Manual for staging of cancer, 2nd edition. Philadelphia, PA: Lippincott Co.; 1983:127-134.
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Outcome related to primary tumor location 0 B. FOWBLE etal.
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