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The significance of the pathology margins of the tumor excision on the outcome of patients treated with definitive irradiation for early stage breast cancer
In, J. Radimon Onm/ogv Bml Phy\ Vol. Printed in the U.S A. All rights reserved
2 I. pp.
0360.3016/91 $3.00 + .oO Copyright B 1991 Pergamon Press plc
279-287
l Original Contribution
THE SIGNIFICANCE OF THE PATHOLOGY MARGINS OF THE TUMOR EXCISION ON THE OUTCOME OF PATIENTS TREATED WITH DEFINITIVE IRRADIATION FOR EARLY STAGE BREAST CANCER LAWRENCE J. SOLIN, M.D.,’ BARBARA L. FOWBLE, M.D.,’ DELRAY J. SCHULTZ, AND ROBERT L. GOODMAN, M.D.’
M.A.2
‘Department of Radiation Oncology, University of Pennsylvania School of Medicine and the Fox Chase Cancer Center; and *Department of Biostatistics, Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA To evaluate the significance of the pathology margins of the tumor excision on the outcome of treatment, an analysis was performed of 697 consecutive women with clinical Stage I or II invasive carcinoma of the breast treated with breast-conserving surgery and definitive irradiation. Complete gross excision of the primary tumor was performed in all cases, and an axillary staging procedure was performed to determine pathologic axillary lymph node status. The 697 patients were divided into four groups based on the final pathology margin from the primary tumor excision or from the re-excision if performed. These four groups were: (a) 257 patients with a negative margin (>2 mm), (b) 57 patients with a positive margin, (c) 37 patients with a close margin (52 mm), and (d) 346 patients with an unknown marght. The patients with positive final pathology margins were focally positive on microscopic examination. Patients with grossly positive margins or with diffusely positive microscopic margins were treated with conversion to mastectomy. There was a significant difference in the total radiation dose for the four groups (median dose of There was no significant difference among the four 6000 vs 6500 vs 6400 vs 6240 cGy, respectively; p < .OOOl). groups for 5year actuarial overall survival (p = .19), no evidence of disease (NED) survival (p = .95), or relapsefree survival (p = X0). There was no significant difference among the four groups for five year actuarial local or regional control (all p 2 .29). Subset analyses did not identify any poor outcome subgroups. These results have demonstrated that selected patients with focally positive or close microscopic pathology margins can be adequately treated with definitive breast irradiation. Patient selection and the technical delivery of radiation treatment including a boost may have been important contributing factors to the good outcome in these patients. Carcinoma of the breast, Definitive breast irradiation, Pathology margins, Lumpectomy,
INTRODUCTION
Breast conservation.
Whereas the presence of a grossly incomplete resection of the primary tumor with an incisional biopsy is an adverse prognostic factor in terms of local control, less information is available relative to the significance of microscopically evaluated pathology margins. In comparison to patients with negative margins, three studies have found higher breast recurrence rates for patients with positive margins with crude breast recurrence rates of 13%-25% (17, 22, 35), whereas three other studies have not found higher breast recurrence rates for patients with positive margins with crude breast recurrence rates of 0%-9% (5, 14, 23). As biopsy specimens are now routinely inked to assess the microscopic pathology margins, the issue of treatment for patients with microscopically positive or
In women treated with breast-conserving surgery and definitive irradiation for early stage carcinoma of the breast, studies have shown that complete gross excision of the primary tumor prior to definitive breast irradiation is important to minimize the rate of local failure (3,4, 13,33). Patients treated with complete gross excision of the primary tumor with an excisional biopsy or wide resection have been reported to have improved local control rates as compared to patients treated with an incisional biopsy or a grossly incompletely resected primary tumor. For patients treated with incisional biopsies, local recurrence rates have been reported as 17%-39% (3, 4, 13, 33).
Presented in part at the Thirty-Second Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Miami Beach, Florida, October 15-19, 1990. Reprint requests to: Lawrence J. Solin, M.D., Department of Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111.
authors thank Ms. Cheryl Vanartsdalen for secretarial assistance in the preparation of this manuscript. Accepted for publication 13 February 1991.
Acknowledgements-The
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close margins is an important consideration in the management of patients with early stage carcinoma of the breast. An early report by our group showed no difference in the local control or survival for patients treated with microscopically positive margins or unknown margins when compared to patients with negative margins on excisional biopsy (30). The present study was undertaken to evaluate the significance of microscopically evaluated pathology margins of the tumor excision in patients treated with definitive breast irradiation and to update our previous report with more patients and longer follow-up (30). METHODS
AND MATERIALS
From 1977 to 1985,697 consecutive women with unilateral carcinoma of the breast were treated with definitive irradiation for early stage breast cancer at the Hospital of the University of Pennsylvania and the Fox Chase Cancer Center. All of the cases had been treated with breast-conserving surgery, and pathologic axillary lymph node staging was performed in all patients. Analysis of cases was limited to patients who had invasive carcinoma of the breast and who were AJC (American Joint Committee) clinical Stage I (Tl NO MO) or clinical Stage II (T2 NO MO, Tl Nl MO, or T2 Nl MO) ( 1). Criteria for patient selection have previously been described in detail (6, 7, 28). Patients with bilateral carcinoma of the breast treated with bilateral definitive breast irradiation were not included and have previously been reported (32). The records of these 697 cases were reviewed for clinical T stage, clinical tumor size, clinical AJC stage, pathologic axillary lymph node status, histology of the primary tumor, first and overall site(s) of failure, estrogen receptor (ER) status, progesterone receptor (PR) status, and menopausal status. The median patient age was 5 1 years (mean = 52 years; range = 22-85 years). The surgical treatment in all cases included complete gross removal of the primary breast carcinoma with an excisional biopsy or wide resection, A re-excisional biopsy was performed in 47% (330/697) of the cases at the time of axillary lymph node surgery. Pathologic axillary lymph node status was determined in general using a lower axillary lymph node dissection of levels I +- II. The final microscopic pathology margin of the tumor excision was determined from review of the pathology reports in the patient records. The final microscopic pathology margin was defined as the margin from the reexcisional biopsy if performed or the margin from the primary tumor excision if a re-excision was not performed. Based on the final microscopic pathology margin, four groups of patients were defined: (a) 257 patients with a negative margin (>2 mm), (b) 57 patients with a positive margin, (c) 37 patients with a close margin (52 mm), and (d) 346 patients with an unknown margin. Patients with no tumor identified on re-excisional biopsy were included within the negative margin group. When pathology margins had been evaluated, the margins of the surgical biopsy
July 1991, Volume 21, Number 2
specimen were inked so that microscopic evaluation could be performed, and orienting sutures had generally been placed by the surgeon at the time of excision so that the location of a positive or close margin could be determined. The margin was scored as positive when tumor was identified at the inked surface of the surgical biopsy specimen. The margin was scored as close when tumor was identified 12 mm from, but not at, the inked surface of the surgical biopsy specimen. The margin was scored as negative when all tumor identified was >2 mm from the inked surface of the surgical biopsy specimen or when no tumor was identified in the re-excisional biopsy specimen. The margin was scored as unknown when the margins of the surgical biopsy specimen were not evaluated. The large number of patients with unknown margins reflects that the routine inking of surgical biopsy specimens was not commonly performed during the early years of the study. The patients with positive microscopic pathology margins were focally positive. Patients with grossly positive margins or diffusely positive microscopic margins were treated with either further re-excision of the primary tumor site or conversion to mastectomy. Radiation treatment policies have previously been described in detail (6,7,28). Whole breast radiotherapy was delivered with opposed tangential fields to 4500-5000 centigray (cGy) over 4f weeks. The radiation energy was generally 6 MV photons, but higher energy photons were used as indicated for patients with large separations or large breast size. The primary tumor bed was boosted to a total dose of 6000-6600 cGy using electrons of varying energy or iridium implants (26,27). The clinical decision as to the total dose was made based on multiple factors including the status of the final pathology margin, whether or not a re-excisional biopsy had been performed, the presence versus absence of residual tumor at the time of re-excisional biopsy, and the volume of the boost field. A total dose of ~6000 cGy was delivered to 93% (649/697) of the patients. Patients with positive axillary lymph nodes were treated with a supraclavicular and apical axillary field to 4600 cGy at a depth of 3 cm, and a posterior axillary boost field was used to bring the mid plane axilla to approximately 4500-4600 cGy (3 1). A supraclavicular field was used in 33% (23 l/697) of the patients. Systemic chemotherapy was delivered to 27% ( 185/697) of the patients (12) and hormonal therapy consisting of tamoxifen was delivered to 6% (41/697) of the patients. Chemotherapy consisted of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) with or without prednisone for 178 patients and other regimens for 7 patients. Survival curves were determined using the KaplanMeier method (16). The Mantel-Cox test was used for statistical comparison between curves (19). The median follow-up time for all 697 cases was 58 months (mean = 6 1 months; range = 2- 137 months). The median follow-up times for the 257 negative margin patients, 57 positive margin patients, 37 close margin patients, and 346 unknown margin patients were 53 months (mean
281
Significance of the pathology margins 0 L. J. SOLINet al.
was 60 months (mean = 63 months: range = 2-137 months). Local failure was defined as a failure that occurred within the treated breast. Regional failure was defined as a failure that occurred in the ipsilateral axillary, supra-
= 52 months; range = 2-l 17 months), 55 months (mean = 56 months; range = 8-97 months), 55 months (mean = 56 months; range = 16-109 months), and 66 months (mean = 68 months; range = 5-l 37 months), respectively. The median follow-up time for surviving patients only
Table 1. Patient and tumor characteristics
Clinical T stage Tl T2 Clinical tumor size 51.0 cm 1.1-2.0 cm 2. I-3.0 cm 3. I-4.0 cm 4.1-5.0 cm Unknown Clinical AJC stage I II Pathologic N stage NO Nl
Re-excisional biopsy Yes No Histology of the primary tumor Ductal Lobular Other Patient age 135 years 36-50 years 25 I years Menopausal status Premenopausal Perimenopausal Postmenopausal Total dose 26000 cGy ~6000 cGy Type of breast boost+ Electrons Iridium implant ER status* Positive Negative PR status* Positive Negative Chemotherapy Yes No Hormonal therapy Yes No
Negative
Positive
Close
Unknown
No. (%)
No. (%)
No. (W)
No. (%)
162 (39) 95 (33)
28 (7) 29 (10)
19 (5) 18 (6)
202 (49) 144 (50)
24 (42) 60 (37) 49 (36) 16 (30) 7 (32) 101 (38)
1 (2) 12 (7) 14 (10) 8 (15) 4 (18) 18 (7)
4 (7) 9 (6) 5 (4) 3 (6) 1 (5) 15 (6)
28 (49) 82 (50) 70 (51) 27 (50) 10 (45) 129 (49)
155 (40) 102 (33)
27 (7) 30 (10)
17 (4) 20 (6)
187 (48) 159 (51)
185 (39) 72 (33)
32 (7) 25 (12)
30 (6) 7 (3)
233 (49) 113 (52)
184 (56) 73 (20)
15 (5) 42 (11)
17 (5) 20 (5)
114 (35) 232 (63)
219 (37) 9 (28) 29 (41)
50 (8) 3 (9) 4 (6)
32 (5) 3 (9) 2 (3)
293 (49) 17 (53) 36 (51)
31 (43) 92 (34) 134 (38)
3 (4) 26 (10) 28 (8)
3 (4) 13 (5) 21 (6)
35 (49) 137 (51) 174 (49)
99 (34) 20 (39) 138 (39)
22 (8) 5 (10) 30 (8)
11 (4) 4 (8) 22 (6)
159 (55) 22 (43) 165 (46)
238 (37) 19 (40)
55 (8) 2 (4)
36 (6) 1 (2)
320 (49) 26 (54)
215 (44) 26 (15)
42 (9) 12 (7)
31 (6) 5 (3)
202 (41) 126 (75)
124 (36) 48 (35)
35 (10) 10 (7)
22 (6) 10 (7)
160 (47) 68 (50)
95 (39) 59 (38)
26 (11) 13 (8)
14 (6) 14 (9)
110 (45) 71 (45)
60 (32) 197 (38)
18 (10) 39 (8)
6 (3) 31 (6)
101 (55) 245 (48)
17 (41) 240 (37)
7 (17) 50 (8)
2 (5) 35 (5)
15 (37) 331 (50)
p value* .17
.62
.73
.04
<.ooo 1
.73
.65
.37
.50
<.ooo 1
.75
.58
.15
.ll
* Chi square test. ’ Includes only cases in which the boost was delivered using electrons or iridium implants and excludes cases in which a boost was not done or in which the boost was delivered using photons or orthovoltage. t Includes only cases in which hormone receptor values were known and excludes cases in which hormone receptor values were not done or unknown.
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July 1991, Volume 21, Number 2
clavicular, infraclavicular, or internal mammary nodal regions. Distant failure was defined as a failure that was beyond local or regional disease. Local-regional failure was defined as a local and/or regional failure. “Local only first failure” was defined as a failure that occurred in the breast as the first and only site of failure without regional failure and without distant failure. “Regional only first failure” was defined as a failure that occurred in the regional nodal areas as the first and only site of failure without local failure and without distant failure. “Local and regional only first failure” was defined as a first failure that occurred in the breast and regional nodal areas as the first sites of failure without distant failure. “Any local failure” was defined as a local failure that occurred at any time during follow-up regardless of regional or distant disease status. “Any local-regional failure” was defined as a local and/or regional failure that occurred at any time during follow-up regardless of distant disease status. “First failure with any local component” was scored as positive for a patient whose first evidence of recurrence included a local failure with or without regional failure and/or distant failure. For analysis of relapse-free survival (RFS), patients were required to be alive and continuously without evidence of disease to not be considered as a failure. For analysis of NED (no evidence of disease) survival, patients were required to be alive and without evidence of disease at the time of last follow-up examination to not be considered as a failure. Therefore, a patient who had been salvaged with further treatment for an isolated local and/or regional failure was considered to be a failure for relapse-free survival, but not a failure for NED survival.
istics is shown in Table 1. The total radiation dose to the primary tumor bed was defined as the sum of the radiation dose from the breast tangential fields plus the radiation dose from the boost field. For the four groups of negative margins, positive margins, close margins, and unknown margins, there was a significant difference in the total dose delivered (median total dose of 6000 cGy vs 6500 cGy vs 6400 cGy vs 6240 cGy, respectively; mean total dose of 6 125 cGy vs 6442 cGy vs 6267 cGy vs 6255 cGy, respectively; p < .OOOl using the Kruskal-Wallis test). There was no significant difference (p = .50) in the percentage of patients in each of the four groups treated to a total dose of 26000 cGy (Table 1). Although an iridium implant boost (75%) was more commonly used than an electron boost (41%) in cases with unknown margins (Table I), this reflects that patients treated with an iridium implant boost and patients with unknown margins were more commonly treated during the earlier years of the study, and patients treated with electron boosts and patients with evaluated margins (i.e., negative, positive or close) were more commonly treated during the later years of the study (p < .OOOl using the chi square test). The 5-year actuarial outcome data for all 697 patients are detailed in Table 2. There was no significant difference in overall, NED, or relapse-free survival outcome at 5 years by final pathology margin (all p 2 .19). There was also no significant difference in the 5-year actuarial outcome for local or local-regional control by final pathology margin (all p 2 .29). Figure 1 shows local failure curves as a function of the final pathology margin. The site(s) of first failure are shown in Table 3. There was no difference in the site(s) of first failure as a function of the final pathology margin (p = .93). A subset analysis was performed of 462 patients treated by radiation therapy only (i.e., patients who had received no chemotherapy, had received no hormonal therapy, and were pathologically node negative). This subset analysis
RESULTS A comparison of the four groups of patients with negative margins, positive margins, close margins, and unknown margins for various patient and tumor character-
Table 2. Five-vear actuarial outcome data for all 697 oatients Five year outcome
Survival Overall NED Relapse-free First failure Local only Regional only Local and regional only Any failure Local Local-regional First failure with any local component * Mantel-Cox
test (19).
(%) by final pathology
margin
Negative (n = 257)
Positive (n = 57)
Close (n = 37)
Unknown (n = 346)
p value*
89 81 75
98 83 81
88 73 69
90 81 75
.I9 .95 .80
6 2 1
0 4 0
10 3 0
7 2 1
.29 .46 .77
7 10
2 8
11 14
9 13
.53 .70
8
2
10
9
.57
Significance
of the pathology
As the use of chemotherapy in patients treated with breast irradiation has been associated with a reduction in the rate of breast recurrence as compared with patients treated without chemotherapy (9, 28), an analysis was performed to evaluate the effect of chemotherapy on the rate of overall breast recurrence (Table 5). For the overall group of 697 patients, there was a reduction in the rate of overall breast recurrence associated with the use of chemotherapy which was of borderline statistical significance (5% with chemotherapy vs 9% without chemotherapy; p = .09). There was no difference in the 5-year actuarial outcome for any local failure for patients with negative
I
25 A
2
1
4
3
5
margins,
YEARS
s 20.
gg
15.
25 z.0 k+
lo-
.
. .I
_ ,--
margins,
or close margins
(all p 2 .18).
10% CLOSE 9% UNKNOWN 8% NEGATIVE
23 z
positive
For patients with unknown final pathology margins, there was a reduction in the 5-year rate of overall breast recurrence which was of borderline statistical significance (2% with chemotherapy vs 11% without chemotherapy: p = .07). However, the analysis of the effect of chemotherapy on breast recurrence was limited by the small number of patients at risk in some of the subgroups evaluated.
25 B i
Et 2%
283
margins 0 L. J. SOLINerul.
DISCUSSION
:-. i ;--__
5-
5 2%
POSITIVE
O-1 0
1
2
3
4
5
YEARS
25 T
6
&
c
i zo-
2 z
15.
!? G >
lo-
10% CLOSE
Fig. I. Local failure as a function of the final pathology margin for all 697 patients. (A) Any local failure. There is no significant difference among the four curves (p = .53). (B) First failure with any local component. There is no significant difference among the four curves (p = .57). (C) Local only first failure. There is no significant difference among the four curves (p = .29).
This report has shown that selected patients with the potentially high risk factors of positive or close microscopic pathology margins from the primary tumor excision can be adequately treated with breast-conserving surgery and definitive irradiation with survival and local control rates equivalent to patients with pathologically confirmed negative margins of the primary tumor excision. The 5-year results for the treatment of the 697 patients with carcinoma of the breast showed no difference in 5-year outcome for survival, local control. or localregional control (Table 2 and Fig. 1). It is likely that careful patient selection was an important contributing factor to the good outcome in the patients with the potentially high risk factors of positive or close margins. The importance of careful evaluation of microscopic pathology margins is to select out patients with grossly positive or diffusely microscopically positive margins for treatment with conversion to mastectomy.
Table 3. Site(s) of first failure Final pathology margin Site(s)
was performed to determine the effect of radiotherapy treatment alone on outcome, and patients treated with chemotherapy or hormonal therapy were excluded from the analysis to avoid any potential confounding effect of chemotherapy or hormonal therapy on local control. Table 4 shows that there was no difference in the 5-year actuarial outcome for overall, NED, or relapse-free survival (all P 2 .67) or for local or local-regional control (all p 2 .28).
Local only Regional only Distant only Local and regional Local and distant
Negative
None
1s 3 30 2 2 2 0 203
Total
257
Regional and distant Local, regional, and distant
p = .93 by
chi square test.
Positive 1 2 I 0 1 1
Clox 4
Unknown
Total
4 0 0
28 4 44 4 3
I
7
4;
21:
I 255
48 10 85 6 6 11 I 530
51
37
346
691
1
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1. J. Radiation Oncology 0 Biology 0 Physics
July 1991, Volume 21, Number 2
Table 4. Five-year actuarial outcome data for the subset of 462 patients treated with radiation only (i.e., no chemotherapy, no hormonal therapy, and pathologically node negative) Five year outcome (%) by final pathology margin
Survival Overall NED Relapse-free First failure Local only Regional only Local and regional only Any failure Local Local-regional First failure with any local component
Negative (n = 175)
Positive (n = 30)
Close (n = 30)
Unknown (n = 227)
p value*
92 85 79
96 74 74
89 77 73
91 85 77
.67 .68 .90
5 1 1
0
5 0
12 3 0
8 1 2
.40 .28 .86
7
0
9
7
14 18
10 13
‘40 .43
7
0
12
10
.54
* Mantel-Cox test (19).
Careful evaluation of the microscopic pathology margins is also important as the radiation treatment technique in the present study was modified based on the findings from the microscopic evaluation of the final pathology margin from the tumor excision. The median total doses were significantly different among the four groups of negative, positive, close, and unknown margins (6000 cGy vs 6500 cGy vs 6400 cGy vs 6240 cGy, respectively; JJ < .OOOl). Customized boost fields using either electron cut-outs or iridium implants were used for each patient. Based on the final pathology margins, wider margins for the boost fields were used in the area of the positive or close margins. However, quantitation of the change in the volume of the boost fields could not be performed, although the difference in dose according to pathology margins was quantifiable. Although our current policy is to use a boost in all patients, careful evaluation of the microscopic pathology margins is necessary to confirm negative margins when a boost dose is not used (8, 9). For the patient who presents without pathologically confirmed negative margins of excision, our current approach is to perform a re-excisional biopsy at the time of axillary lymph node dissection to obtain pathologically Table 5. The effect of chemotherapy
confirmed negative margins. If the patient has grossly positive or diffusely positive final pathology margins, conversion to mastectomy is performed. For the patient who is to undergo definitive breast irradiation with a focally positive microscopic margin, a focally close microscopic margin, or an unknown microscopic margin, higher total radiation doses (6400-6600 cGy) are used depending on the status of the margins, and a wider margin for the boost field is used in the area of the close or positive margin. Patients treated with grossly incomplete excision of the primary tumor are at significantly higher risk of local failure than are patients treated with grossly complete excision of the primary tumor (3, 4, 13, 33). However, relatively little information is available as to the outcome of patients treated with definitive breast irradiation as a function of the microscopic pathology margin of the tumor excision. Table 6 summarizes series from the literature which have reported breast recurrence as a function of the pathology margin of the tumor excision. Patients with a microscopically positive or close margin from the primary tumor excision have been noted to have variable results in the literature as compared to patients with negative margins.
on the five year actuarial outcome for any local failure
Chemotherapy
No chemotherapy
Final pathology margin
Number of patients
Any local failure at 5 years (%)
Number of patients
Any local failure at 5 years (W)
p value*
Negative Positive Close Unknown
60 18 6 101
12 6 0 2
197 39 31 245
7 0 14 11
.96 .55 .18 .07
Overall
185
5
512
9
.09
* Mantel-Cox test (19).
285
Significance of the pathology margins 0 L. J. SOLIN el ul. Table 6. Review of series reporting breast recurrence as a function of the pathology margin of the tumor excision Crude breast recurrence (%) by pathology margin
5-year actuarial breast recurrence (%) by pathology margin Author
Total number of patients
Bartelink et al. (2) Clarke et al. (5) Fisher et al. (9) Hunig et al. (14) Kurtz et al. (17) Ryoo et al. (22) Schmidt-Ullrich et al. (23) Zafrani et al. (35) Solin et al. (present series)
Negative
Positive
Close
Unknown
Negative
Positive
Close
Unknown
585 362 569 105 496 393
2* 5* -
6* -
4* -
-
4 I 8 6
-
-
(
114 433
9’
2;+
-
-
0 8
0 25
697
I
2
11
I
5
* Estimated from curves.
In comparison to breast recurrence rates for patients with negative margins, three studies have found higher breast recurrence rates for patients with positive margins with crude breast recurrence rates of 13%-25% (17, 22, 35)
whereas three other studies have found no higher breast recurrence rates for patients with positive margins with crude breast recurrence rates of 0%-9% (5, 14,23). In the study of Kurtz et al. (17), analysis of the margins was performed retrospectively, and inking of the margins had not been performed. In the study of Zafrani et al. (35) margins were defined as positive on gross examination or on microscopic pathology examination. Fisher et al. (9) reported an g-year actuarial breast recurrence rate of 10% in patients with pathologically confirmed negative margins, and the patients in that study were treated with whole breast radiotherapy without a boost to the primary tumor site. In patients who have undergone complete gross excision of the primary tumor, there is a significant incidence of microscopically positive margins at the time of pathologic evaluation of the biopsy specimen. Fisher et al. (8) reported that 10% of 1257 patients treated by lumpectomy were found to have microscopically positive margins. Of the 63 1 patients in the present study treated with complete gross excision of the primary tumor at the time of initial excision (i.e., excluding initial incisional biopsies and excluding re-excisional biopsies), 13% (80/63 1) were found to have a positive margin on initial biopsy, and 4% (23/ 63 1) were found to have a close margin on initial biopsy. Other studies have also noted significant rates of microscopically positive margins after excisional biopsy of the primary tumor with an incidence of 9%-28% (2,5,8, 14, 18, 20, 29, 34). Patients with clinical T-2 lesions have been reported to have a positive margin of resection more frequently than patients with clinical T- 1 lesions (8, 14, 20). Schnitt et al. (24) found that the microscopic margins from the primary tumor excision were positive in 95% of the cases with EIC (extensive intraductal component) present as compared to 65% without EIC present. Al-
9
9 7 24 13
8 0
0
-
-
14
11
+At 10 years.
though the incidence of microscopically positive margins of resection decreases as the biopsy procedure progresses from lumpectomy to wide excision to quadrantectomy ( 11, 15, 34), this must be balanced against the ability of the radiation oncologist to obtain adequate local control in the presence of a focally microscopically positive or close margin as well as the possibility of less than optimal cosmesis with a wide excision or quadrantectomy. Re-excisional biopsy procedures have become more commonly used in an attempt to obtain pathologically confirmed negative margins of tumor resection. The incidence of residual tumor at the time of re-excisional biopsy has been found to be 32%-62% (20,2 1,24, 25,29). In a previous report by our group, the incidence of residual tumor on re-excisional biopsy was found to be 60% for patients with positive margins on initial excision and 49% for patients with unknown margins on initial excision (29). The incidence of positive re-excisions for patients with positive initial biopsy margins has been reported as being 55% by McCormick et al. (20) and 69% by Schnitt et al. (24). Frazier et al. (10) reported that there was residual tumor at the time of re-excision or mastectomy in 53% of patients with positive margins on initial biopsy. Two studies have found that the incidence of residual tumor for patients with an initially negative margin of resection was 33% as reported by Schnitt et al. (24) and 26% as reported by Frazier et al. (10). Other factors have been associated with high rates of residual carcinoma on re-excision. Solin et al. (29) reported that there was residual carcinoma on re-excision in 86% of patients who were found to have residual microcalcifications on a post-biopsy mammogram. Schnitt et al. (24) reported that patients with extensive intraductal component (EIC) on initial biopsy were found to have an 88% incidence of residual carcinoma at the time of re-excision. Factors which have been proposed as indications for a re-excisional biopsy prior to definitive breast irradiation include initial positive margins (20, 24, 29) initial unknown margins (29) residual microcalcifications on post-biopsy mammogram
286
I. J. Radiation Oncology 0 Biology 0 Physics
(29) the presence of extensive intraductal component (EIC) (24) and a biopsy elsewhere (i.e., outside of the treatment institution) (2 1, 25). In summary, the present study has demonstrated adequate local control and survival in selected patients with
July 1991. Volume 21. Number 2
the potentially high risk factors of positive or close microscopic pathology margins. Patient selection and the technical delivery of the radiotherapy including a boost may have been important contributing factors to the good outcome in these potentially high risk groups.
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7.
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9.
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J. L. The impact of tumor size and histology on local control after breast-conserving therapy. Radiother. Oncol. 11:297303; 1988. Bedwinek, J. M.; Perez, C. A.; Kramer, S.; Brady, L.; Goodman, R.; Grundy, G. Irradiation as the primary management of Stage I and II adenocarcinoma of the breast: analysis of the RTOG breast registry. Cancer Clin. Trials 3: 1 l-l 8; 1980. Chu, A. M.; Cope, 0.; Russo, R.; Lew, R. Patterns of localregional recurrence and results in Stages I and II breast cancer treated by irradiation following limited surgery: an update. Am. J. Clin. Oncol. (Cancer Clin. Trials) 7:22 l-229; 1984. Clarke, D. H.; Le, M. G.; Sarrazin, D.; Lacombe, M. J.; Fontaine, F.; Travagli, J. P.; May-Levin, F.; Contesso, G.; Arriagada, R. Analysis of local-regional relapses in patients with early breast cancers treated by excision and radiotherapy: experience of the Institut Gustave-Roussy. Int. J. Radiat. Oncol. Biol. Phys. 11:137-145; 1985. Danoff, B. F.; Haller, D. G.; Click, J. H.; Goodman, R. L. Conservative surgery and irradiation in the treatment of early breast cancer. Ann. Intern. Med. 102:634-642: 1985. Danoff, B. F.; Pajak, T. F.; Solin, L. J.; Goodman, R. L. Excisional biopsy, axillary node dissection and definitive radiotherapy for stages I and II breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 11:479-483; 1985. Fisher, B.; Bauer, M.; Margolese, R.; Poisson, R.; Pilch, Y.; Redmond, C.; Fisher, E.; Wolmark, N.; Deutsch, M.; Montague, E.; Saffer, E.; Wickerham, L.; Lerner, H.; Glass, A.: Shibata, H.; Deckers, P.; Ketcham, A.; Oishi, R.; Russell, I. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N. Engl. J. Med. 312:665-673; 1985. Fisher, B.; Redmond, C.; Poisson, R.; Margolese, R.; Wolmark, N.; Wickerham, L.; Fisher, E.; Deutsch, M.; Caplan, R.; Pilch, Y.; Glass, A.; Shibata, H.; Lerner, H.; Terz, J.; Sidorovich, L. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N. EngI. J. Med. 320:822-828; 1989. Frazier, T. G.; Wong, R. W. Y.; Rose, D. Implications of accurate pathologic margins in the treatment of primary breast cancer. Arch. Surg. 124:37-38; 1989. Ghossein, N. A.; Barba, J. P.; Alpett, S.; Pressman, P.; Stacey, P.; Sadarangani, G. Importance of adequate surgical excision prior to radiotherapy in the local control of patients treated conservatively for breast cancer (Abstr.). Proc 17th International Congress of Radiology, Paris, France, 1989; 48. Click, J. H.; Danoff, B. F.; Haller, D. G.; Weiler, C.; Goodman, R. L. Adjuvant chemotherapy in patients undergoing definitive irradiation for primary breast cancer-the University of Pennsylvania experience. In: Harris, J. R.; Hellman, S., Silen, W., eds. Conservative management of breast
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cancer: new surgical and radiotherapeutic techniques. Philadelphia, PA: J.B. Lippincott Co. 1983:3 1 l-320. Harris, J. R.; Botnick, L.; Bloomer, W. D.; Chaffey, J. T.: Hellman, S. Primary radiation therapy for early breast cancer: the experience at the Joint Center for Radiation Therapy. lnt. J. Radiat. Oncol. Biol. Phys. 7: 1549-l 552; 198 1. Hunig, R.; Walther, E.; Harder, F. H.; Almendral, A. C.: Roth, J.; Torhorst, J. The Base1 lumpectomy protocol: liveyear experience with a prospective study for conservative treatment of breast cancer. In: Harris, J. R.; Hellman, S., Silen, W., eds. Conservative management of breast cancer: new surgical and radiotherapeutic techniques. Philadelphia, PA: J.B. Lippincott Co. 1983:23-33. Kantorowitz, D. A.; Pouher, C. A.; Rubin, P.; Patterson, E.; Sobel, S. H.; Sischy, B.; Dvoretsky, P. M.; Michalak, W. A.; Doane, K. Treatment of breast cancer with segmental mastectomy alone or segmental mastectomy plus radiation. Radiother. Oncol. 15: 14 1- 150; 1989. Kapian, E. L.; Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53:457-481, 1958. Kurtz, J. M.; Jacquemier, J.; Amalric, R.; Brandone, H.; Ayme, Y.; Hans, D.; Bressac, C.; Spitalier, J.-M. Why are local recurrences after breast conserving therapy more frequent in young patients? J. Clin. Oncol. 8:591-598; 1990. Lagios, M. D.; Richards, V. E.; Rose, M. R.; Yee, E. Segmental mastectomy without radiotherapy: short-term follow-up. Cancer 52:2 173-2 179; 1983. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 50: 163- 170; 1966. McCormick, B.; Kinne, D.; Petrek, J.; Osborne, M.; Cox, L.; Shank, B.; Hellman, S.; Yahalom, J.; Rosen, P. P. Limited resection for breast cancer: a study of inked specimen margins before radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 13:1667-1671; 1987. Montague, E. D. Conservation surgery and radiation therapy in the treatment of operable breast cancer. Cancer 53:700704; 1984. Ryoo, M. C.; Kagan, A. R.; Wollin, M.; Tome, M. A.: Tedeschi, M. A.; Rao, A. R.; Hintz, B. L.; Kuruvilla, A. M.; Nussbaum, H.; Streeter, 0. E.; Jabola, B. R.; Miller, M. J. Prognostic factors for recurrence and cosmesis in 393 patients after radiation therapy for early mammary carcinoma. Radiology 1721555-559; 1989. Schmidt-Ulh-ich, R.; Wazer, D. E.; Tercilla, 0.; Safaii, H.; Marchant, D. J.; Smith, T. J.; Homer, M. A.; Robert, N. J. Tumor margin assessment as a guide to optimal conservation surgery and irradiation in early stage breast carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 17:733-738; 1989. Schnitt, S. J.; Connolly, J. L.; Khettry, U.; Mazoujian, G.; Brenner, M.; Silver, B.; Recht, A.; Beadle, G.; Harris, J. R. Pathologic findings on re-excision of the primary site in breast cancer patients considered for treatment by primary radiation therapy. Cancer 59:675-68 1; 1987. Schwartz, G. F.; Rosenberg, A. L.; Danoff, B. F.; Mansfield, C. M.; Feig, S. A. Lumpectomy and level 1 axillary dissection
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prior to irradiation for “operable” breast cancer. Ann. Surg. 200:554-560; 1984. Solin, L. J.; Chu, J. C. H.; Larsen, R.; Fowble, B.; Galvin, J. M.; Goodman, R. L. Determination of depth for electron breast boosts. Int. J. Radiat. Oncol. Biol. Phys. 13: 19 151919; 1987. Solin, L. J.; Danoff, B. F.; Schwartz, G. F.; Galvin, J. M.: Goodman, R. L. A practical technique for the localization of the tumor volume in definitive irradiation of the breast. lnt. J. Radiat. Oncol. Biol. Phys. 11:1215-1220; 1985. Solin, L. J.; Fowble, B.; Martz, K. L.; Goodman, R. L. Definitive irradiation for early stage breast cancer: the University of Pennsylvania experience. Int. J. Radiat. Oncol. Biol. Phys. 14:235-242; 1988. Solin. L. J.; Fowble, B.; Martz, K.; Pajak, T. F.; Goodman, R. L. Results of re-excisional biopsy of the primary tumor in preparation for definitive irradiation of patients with early stage breast cancer. lnt. J. Radiat. Oncol. Biol. Phys. 12: 721-725: 1986. Solin. L. J.: Fowble, B.; Martz, K. L.; Pajak, T. F.; Goodman, R. L. Does residual tumor adversely impact on the outcome of patients undergoing definitive irradiation for early stage breast cancer? (Abstr.). lnt. J. Radiat. Oncol. Biol. Phys. lZ(Suppl. 1):91-92, 1986.
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2 I. pp.
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l Original Contribution
THE SIGNIFICANCE OF THE PATHOLOGY MARGINS OF THE TUMOR EXCISION ON THE OUTCOME OF PATIENTS TREATED WITH DEFINITIVE IRRADIATION FOR EARLY STAGE BREAST CANCER LAWRENCE J. SOLIN, M.D.,’ BARBARA L. FOWBLE, M.D.,’ DELRAY J. SCHULTZ, AND ROBERT L. GOODMAN, M.D.’
M.A.2
‘Department of Radiation Oncology, University of Pennsylvania School of Medicine and the Fox Chase Cancer Center; and *Department of Biostatistics, Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA To evaluate the significance of the pathology margins of the tumor excision on the outcome of treatment, an analysis was performed of 697 consecutive women with clinical Stage I or II invasive carcinoma of the breast treated with breast-conserving surgery and definitive irradiation. Complete gross excision of the primary tumor was performed in all cases, and an axillary staging procedure was performed to determine pathologic axillary lymph node status. The 697 patients were divided into four groups based on the final pathology margin from the primary tumor excision or from the re-excision if performed. These four groups were: (a) 257 patients with a negative margin (>2 mm), (b) 57 patients with a positive margin, (c) 37 patients with a close margin (52 mm), and (d) 346 patients with an unknown marght. The patients with positive final pathology margins were focally positive on microscopic examination. Patients with grossly positive margins or with diffusely positive microscopic margins were treated with conversion to mastectomy. There was a significant difference in the total radiation dose for the four groups (median dose of There was no significant difference among the four 6000 vs 6500 vs 6400 vs 6240 cGy, respectively; p < .OOOl). groups for 5year actuarial overall survival (p = .19), no evidence of disease (NED) survival (p = .95), or relapsefree survival (p = X0). There was no significant difference among the four groups for five year actuarial local or regional control (all p 2 .29). Subset analyses did not identify any poor outcome subgroups. These results have demonstrated that selected patients with focally positive or close microscopic pathology margins can be adequately treated with definitive breast irradiation. Patient selection and the technical delivery of radiation treatment including a boost may have been important contributing factors to the good outcome in these patients. Carcinoma of the breast, Definitive breast irradiation, Pathology margins, Lumpectomy,
INTRODUCTION
Breast conservation.
Whereas the presence of a grossly incomplete resection of the primary tumor with an incisional biopsy is an adverse prognostic factor in terms of local control, less information is available relative to the significance of microscopically evaluated pathology margins. In comparison to patients with negative margins, three studies have found higher breast recurrence rates for patients with positive margins with crude breast recurrence rates of 13%-25% (17, 22, 35), whereas three other studies have not found higher breast recurrence rates for patients with positive margins with crude breast recurrence rates of 0%-9% (5, 14, 23). As biopsy specimens are now routinely inked to assess the microscopic pathology margins, the issue of treatment for patients with microscopically positive or
In women treated with breast-conserving surgery and definitive irradiation for early stage carcinoma of the breast, studies have shown that complete gross excision of the primary tumor prior to definitive breast irradiation is important to minimize the rate of local failure (3,4, 13,33). Patients treated with complete gross excision of the primary tumor with an excisional biopsy or wide resection have been reported to have improved local control rates as compared to patients treated with an incisional biopsy or a grossly incompletely resected primary tumor. For patients treated with incisional biopsies, local recurrence rates have been reported as 17%-39% (3, 4, 13, 33).
Presented in part at the Thirty-Second Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Miami Beach, Florida, October 15-19, 1990. Reprint requests to: Lawrence J. Solin, M.D., Department of Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111.
authors thank Ms. Cheryl Vanartsdalen for secretarial assistance in the preparation of this manuscript. Accepted for publication 13 February 1991.
Acknowledgements-The
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close margins is an important consideration in the management of patients with early stage carcinoma of the breast. An early report by our group showed no difference in the local control or survival for patients treated with microscopically positive margins or unknown margins when compared to patients with negative margins on excisional biopsy (30). The present study was undertaken to evaluate the significance of microscopically evaluated pathology margins of the tumor excision in patients treated with definitive breast irradiation and to update our previous report with more patients and longer follow-up (30). METHODS
AND MATERIALS
From 1977 to 1985,697 consecutive women with unilateral carcinoma of the breast were treated with definitive irradiation for early stage breast cancer at the Hospital of the University of Pennsylvania and the Fox Chase Cancer Center. All of the cases had been treated with breast-conserving surgery, and pathologic axillary lymph node staging was performed in all patients. Analysis of cases was limited to patients who had invasive carcinoma of the breast and who were AJC (American Joint Committee) clinical Stage I (Tl NO MO) or clinical Stage II (T2 NO MO, Tl Nl MO, or T2 Nl MO) ( 1). Criteria for patient selection have previously been described in detail (6, 7, 28). Patients with bilateral carcinoma of the breast treated with bilateral definitive breast irradiation were not included and have previously been reported (32). The records of these 697 cases were reviewed for clinical T stage, clinical tumor size, clinical AJC stage, pathologic axillary lymph node status, histology of the primary tumor, first and overall site(s) of failure, estrogen receptor (ER) status, progesterone receptor (PR) status, and menopausal status. The median patient age was 5 1 years (mean = 52 years; range = 22-85 years). The surgical treatment in all cases included complete gross removal of the primary breast carcinoma with an excisional biopsy or wide resection, A re-excisional biopsy was performed in 47% (330/697) of the cases at the time of axillary lymph node surgery. Pathologic axillary lymph node status was determined in general using a lower axillary lymph node dissection of levels I +- II. The final microscopic pathology margin of the tumor excision was determined from review of the pathology reports in the patient records. The final microscopic pathology margin was defined as the margin from the reexcisional biopsy if performed or the margin from the primary tumor excision if a re-excision was not performed. Based on the final microscopic pathology margin, four groups of patients were defined: (a) 257 patients with a negative margin (>2 mm), (b) 57 patients with a positive margin, (c) 37 patients with a close margin (52 mm), and (d) 346 patients with an unknown margin. Patients with no tumor identified on re-excisional biopsy were included within the negative margin group. When pathology margins had been evaluated, the margins of the surgical biopsy
July 1991, Volume 21, Number 2
specimen were inked so that microscopic evaluation could be performed, and orienting sutures had generally been placed by the surgeon at the time of excision so that the location of a positive or close margin could be determined. The margin was scored as positive when tumor was identified at the inked surface of the surgical biopsy specimen. The margin was scored as close when tumor was identified 12 mm from, but not at, the inked surface of the surgical biopsy specimen. The margin was scored as negative when all tumor identified was >2 mm from the inked surface of the surgical biopsy specimen or when no tumor was identified in the re-excisional biopsy specimen. The margin was scored as unknown when the margins of the surgical biopsy specimen were not evaluated. The large number of patients with unknown margins reflects that the routine inking of surgical biopsy specimens was not commonly performed during the early years of the study. The patients with positive microscopic pathology margins were focally positive. Patients with grossly positive margins or diffusely positive microscopic margins were treated with either further re-excision of the primary tumor site or conversion to mastectomy. Radiation treatment policies have previously been described in detail (6,7,28). Whole breast radiotherapy was delivered with opposed tangential fields to 4500-5000 centigray (cGy) over 4f weeks. The radiation energy was generally 6 MV photons, but higher energy photons were used as indicated for patients with large separations or large breast size. The primary tumor bed was boosted to a total dose of 6000-6600 cGy using electrons of varying energy or iridium implants (26,27). The clinical decision as to the total dose was made based on multiple factors including the status of the final pathology margin, whether or not a re-excisional biopsy had been performed, the presence versus absence of residual tumor at the time of re-excisional biopsy, and the volume of the boost field. A total dose of ~6000 cGy was delivered to 93% (649/697) of the patients. Patients with positive axillary lymph nodes were treated with a supraclavicular and apical axillary field to 4600 cGy at a depth of 3 cm, and a posterior axillary boost field was used to bring the mid plane axilla to approximately 4500-4600 cGy (3 1). A supraclavicular field was used in 33% (23 l/697) of the patients. Systemic chemotherapy was delivered to 27% ( 185/697) of the patients (12) and hormonal therapy consisting of tamoxifen was delivered to 6% (41/697) of the patients. Chemotherapy consisted of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) with or without prednisone for 178 patients and other regimens for 7 patients. Survival curves were determined using the KaplanMeier method (16). The Mantel-Cox test was used for statistical comparison between curves (19). The median follow-up time for all 697 cases was 58 months (mean = 6 1 months; range = 2- 137 months). The median follow-up times for the 257 negative margin patients, 57 positive margin patients, 37 close margin patients, and 346 unknown margin patients were 53 months (mean
281
Significance of the pathology margins 0 L. J. SOLINet al.
was 60 months (mean = 63 months: range = 2-137 months). Local failure was defined as a failure that occurred within the treated breast. Regional failure was defined as a failure that occurred in the ipsilateral axillary, supra-
= 52 months; range = 2-l 17 months), 55 months (mean = 56 months; range = 8-97 months), 55 months (mean = 56 months; range = 16-109 months), and 66 months (mean = 68 months; range = 5-l 37 months), respectively. The median follow-up time for surviving patients only
Table 1. Patient and tumor characteristics
Clinical T stage Tl T2 Clinical tumor size 51.0 cm 1.1-2.0 cm 2. I-3.0 cm 3. I-4.0 cm 4.1-5.0 cm Unknown Clinical AJC stage I II Pathologic N stage NO Nl
Re-excisional biopsy Yes No Histology of the primary tumor Ductal Lobular Other Patient age 135 years 36-50 years 25 I years Menopausal status Premenopausal Perimenopausal Postmenopausal Total dose 26000 cGy ~6000 cGy Type of breast boost+ Electrons Iridium implant ER status* Positive Negative PR status* Positive Negative Chemotherapy Yes No Hormonal therapy Yes No
Negative
Positive
Close
Unknown
No. (%)
No. (%)
No. (W)
No. (%)
162 (39) 95 (33)
28 (7) 29 (10)
19 (5) 18 (6)
202 (49) 144 (50)
24 (42) 60 (37) 49 (36) 16 (30) 7 (32) 101 (38)
1 (2) 12 (7) 14 (10) 8 (15) 4 (18) 18 (7)
4 (7) 9 (6) 5 (4) 3 (6) 1 (5) 15 (6)
28 (49) 82 (50) 70 (51) 27 (50) 10 (45) 129 (49)
155 (40) 102 (33)
27 (7) 30 (10)
17 (4) 20 (6)
187 (48) 159 (51)
185 (39) 72 (33)
32 (7) 25 (12)
30 (6) 7 (3)
233 (49) 113 (52)
184 (56) 73 (20)
15 (5) 42 (11)
17 (5) 20 (5)
114 (35) 232 (63)
219 (37) 9 (28) 29 (41)
50 (8) 3 (9) 4 (6)
32 (5) 3 (9) 2 (3)
293 (49) 17 (53) 36 (51)
31 (43) 92 (34) 134 (38)
3 (4) 26 (10) 28 (8)
3 (4) 13 (5) 21 (6)
35 (49) 137 (51) 174 (49)
99 (34) 20 (39) 138 (39)
22 (8) 5 (10) 30 (8)
11 (4) 4 (8) 22 (6)
159 (55) 22 (43) 165 (46)
238 (37) 19 (40)
55 (8) 2 (4)
36 (6) 1 (2)
320 (49) 26 (54)
215 (44) 26 (15)
42 (9) 12 (7)
31 (6) 5 (3)
202 (41) 126 (75)
124 (36) 48 (35)
35 (10) 10 (7)
22 (6) 10 (7)
160 (47) 68 (50)
95 (39) 59 (38)
26 (11) 13 (8)
14 (6) 14 (9)
110 (45) 71 (45)
60 (32) 197 (38)
18 (10) 39 (8)
6 (3) 31 (6)
101 (55) 245 (48)
17 (41) 240 (37)
7 (17) 50 (8)
2 (5) 35 (5)
15 (37) 331 (50)
p value* .17
.62
.73
.04
<.ooo 1
.73
.65
.37
.50
<.ooo 1
.75
.58
.15
.ll
* Chi square test. ’ Includes only cases in which the boost was delivered using electrons or iridium implants and excludes cases in which a boost was not done or in which the boost was delivered using photons or orthovoltage. t Includes only cases in which hormone receptor values were known and excludes cases in which hormone receptor values were not done or unknown.
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July 1991, Volume 21, Number 2
clavicular, infraclavicular, or internal mammary nodal regions. Distant failure was defined as a failure that was beyond local or regional disease. Local-regional failure was defined as a local and/or regional failure. “Local only first failure” was defined as a failure that occurred in the breast as the first and only site of failure without regional failure and without distant failure. “Regional only first failure” was defined as a failure that occurred in the regional nodal areas as the first and only site of failure without local failure and without distant failure. “Local and regional only first failure” was defined as a first failure that occurred in the breast and regional nodal areas as the first sites of failure without distant failure. “Any local failure” was defined as a local failure that occurred at any time during follow-up regardless of regional or distant disease status. “Any local-regional failure” was defined as a local and/or regional failure that occurred at any time during follow-up regardless of distant disease status. “First failure with any local component” was scored as positive for a patient whose first evidence of recurrence included a local failure with or without regional failure and/or distant failure. For analysis of relapse-free survival (RFS), patients were required to be alive and continuously without evidence of disease to not be considered as a failure. For analysis of NED (no evidence of disease) survival, patients were required to be alive and without evidence of disease at the time of last follow-up examination to not be considered as a failure. Therefore, a patient who had been salvaged with further treatment for an isolated local and/or regional failure was considered to be a failure for relapse-free survival, but not a failure for NED survival.
istics is shown in Table 1. The total radiation dose to the primary tumor bed was defined as the sum of the radiation dose from the breast tangential fields plus the radiation dose from the boost field. For the four groups of negative margins, positive margins, close margins, and unknown margins, there was a significant difference in the total dose delivered (median total dose of 6000 cGy vs 6500 cGy vs 6400 cGy vs 6240 cGy, respectively; mean total dose of 6 125 cGy vs 6442 cGy vs 6267 cGy vs 6255 cGy, respectively; p < .OOOl using the Kruskal-Wallis test). There was no significant difference (p = .50) in the percentage of patients in each of the four groups treated to a total dose of 26000 cGy (Table 1). Although an iridium implant boost (75%) was more commonly used than an electron boost (41%) in cases with unknown margins (Table I), this reflects that patients treated with an iridium implant boost and patients with unknown margins were more commonly treated during the earlier years of the study, and patients treated with electron boosts and patients with evaluated margins (i.e., negative, positive or close) were more commonly treated during the later years of the study (p < .OOOl using the chi square test). The 5-year actuarial outcome data for all 697 patients are detailed in Table 2. There was no significant difference in overall, NED, or relapse-free survival outcome at 5 years by final pathology margin (all p 2 .19). There was also no significant difference in the 5-year actuarial outcome for local or local-regional control by final pathology margin (all p 2 .29). Figure 1 shows local failure curves as a function of the final pathology margin. The site(s) of first failure are shown in Table 3. There was no difference in the site(s) of first failure as a function of the final pathology margin (p = .93). A subset analysis was performed of 462 patients treated by radiation therapy only (i.e., patients who had received no chemotherapy, had received no hormonal therapy, and were pathologically node negative). This subset analysis
RESULTS A comparison of the four groups of patients with negative margins, positive margins, close margins, and unknown margins for various patient and tumor character-
Table 2. Five-vear actuarial outcome data for all 697 oatients Five year outcome
Survival Overall NED Relapse-free First failure Local only Regional only Local and regional only Any failure Local Local-regional First failure with any local component * Mantel-Cox
test (19).
(%) by final pathology
margin
Negative (n = 257)
Positive (n = 57)
Close (n = 37)
Unknown (n = 346)
p value*
89 81 75
98 83 81
88 73 69
90 81 75
.I9 .95 .80
6 2 1
0 4 0
10 3 0
7 2 1
.29 .46 .77
7 10
2 8
11 14
9 13
.53 .70
8
2
10
9
.57
Significance
of the pathology
As the use of chemotherapy in patients treated with breast irradiation has been associated with a reduction in the rate of breast recurrence as compared with patients treated without chemotherapy (9, 28), an analysis was performed to evaluate the effect of chemotherapy on the rate of overall breast recurrence (Table 5). For the overall group of 697 patients, there was a reduction in the rate of overall breast recurrence associated with the use of chemotherapy which was of borderline statistical significance (5% with chemotherapy vs 9% without chemotherapy; p = .09). There was no difference in the 5-year actuarial outcome for any local failure for patients with negative
I
25 A
2
1
4
3
5
margins,
YEARS
s 20.
gg
15.
25 z.0 k+
lo-
.
. .I
_ ,--
margins,
or close margins
(all p 2 .18).
10% CLOSE 9% UNKNOWN 8% NEGATIVE
23 z
positive
For patients with unknown final pathology margins, there was a reduction in the 5-year rate of overall breast recurrence which was of borderline statistical significance (2% with chemotherapy vs 11% without chemotherapy: p = .07). However, the analysis of the effect of chemotherapy on breast recurrence was limited by the small number of patients at risk in some of the subgroups evaluated.
25 B i
Et 2%
283
margins 0 L. J. SOLINerul.
DISCUSSION
:-. i ;--__
5-
5 2%
POSITIVE
O-1 0
1
2
3
4
5
YEARS
25 T
6
&
c
i zo-
2 z
15.
!? G >
lo-
10% CLOSE
Fig. I. Local failure as a function of the final pathology margin for all 697 patients. (A) Any local failure. There is no significant difference among the four curves (p = .53). (B) First failure with any local component. There is no significant difference among the four curves (p = .57). (C) Local only first failure. There is no significant difference among the four curves (p = .29).
This report has shown that selected patients with the potentially high risk factors of positive or close microscopic pathology margins from the primary tumor excision can be adequately treated with breast-conserving surgery and definitive irradiation with survival and local control rates equivalent to patients with pathologically confirmed negative margins of the primary tumor excision. The 5-year results for the treatment of the 697 patients with carcinoma of the breast showed no difference in 5-year outcome for survival, local control. or localregional control (Table 2 and Fig. 1). It is likely that careful patient selection was an important contributing factor to the good outcome in the patients with the potentially high risk factors of positive or close margins. The importance of careful evaluation of microscopic pathology margins is to select out patients with grossly positive or diffusely microscopically positive margins for treatment with conversion to mastectomy.
Table 3. Site(s) of first failure Final pathology margin Site(s)
was performed to determine the effect of radiotherapy treatment alone on outcome, and patients treated with chemotherapy or hormonal therapy were excluded from the analysis to avoid any potential confounding effect of chemotherapy or hormonal therapy on local control. Table 4 shows that there was no difference in the 5-year actuarial outcome for overall, NED, or relapse-free survival (all P 2 .67) or for local or local-regional control (all p 2 .28).
Local only Regional only Distant only Local and regional Local and distant
Negative
None
1s 3 30 2 2 2 0 203
Total
257
Regional and distant Local, regional, and distant
p = .93 by
chi square test.
Positive 1 2 I 0 1 1
Clox 4
Unknown
Total
4 0 0
28 4 44 4 3
I
7
4;
21:
I 255
48 10 85 6 6 11 I 530
51
37
346
691
1
284
1. J. Radiation Oncology 0 Biology 0 Physics
July 1991, Volume 21, Number 2
Table 4. Five-year actuarial outcome data for the subset of 462 patients treated with radiation only (i.e., no chemotherapy, no hormonal therapy, and pathologically node negative) Five year outcome (%) by final pathology margin
Survival Overall NED Relapse-free First failure Local only Regional only Local and regional only Any failure Local Local-regional First failure with any local component
Negative (n = 175)
Positive (n = 30)
Close (n = 30)
Unknown (n = 227)
p value*
92 85 79
96 74 74
89 77 73
91 85 77
.67 .68 .90
5 1 1
0
5 0
12 3 0
8 1 2
.40 .28 .86
7
0
9
7
14 18
10 13
‘40 .43
7
0
12
10
.54
* Mantel-Cox test (19).
Careful evaluation of the microscopic pathology margins is also important as the radiation treatment technique in the present study was modified based on the findings from the microscopic evaluation of the final pathology margin from the tumor excision. The median total doses were significantly different among the four groups of negative, positive, close, and unknown margins (6000 cGy vs 6500 cGy vs 6400 cGy vs 6240 cGy, respectively; JJ < .OOOl). Customized boost fields using either electron cut-outs or iridium implants were used for each patient. Based on the final pathology margins, wider margins for the boost fields were used in the area of the positive or close margins. However, quantitation of the change in the volume of the boost fields could not be performed, although the difference in dose according to pathology margins was quantifiable. Although our current policy is to use a boost in all patients, careful evaluation of the microscopic pathology margins is necessary to confirm negative margins when a boost dose is not used (8, 9). For the patient who presents without pathologically confirmed negative margins of excision, our current approach is to perform a re-excisional biopsy at the time of axillary lymph node dissection to obtain pathologically Table 5. The effect of chemotherapy
confirmed negative margins. If the patient has grossly positive or diffusely positive final pathology margins, conversion to mastectomy is performed. For the patient who is to undergo definitive breast irradiation with a focally positive microscopic margin, a focally close microscopic margin, or an unknown microscopic margin, higher total radiation doses (6400-6600 cGy) are used depending on the status of the margins, and a wider margin for the boost field is used in the area of the close or positive margin. Patients treated with grossly incomplete excision of the primary tumor are at significantly higher risk of local failure than are patients treated with grossly complete excision of the primary tumor (3, 4, 13, 33). However, relatively little information is available as to the outcome of patients treated with definitive breast irradiation as a function of the microscopic pathology margin of the tumor excision. Table 6 summarizes series from the literature which have reported breast recurrence as a function of the pathology margin of the tumor excision. Patients with a microscopically positive or close margin from the primary tumor excision have been noted to have variable results in the literature as compared to patients with negative margins.
on the five year actuarial outcome for any local failure
Chemotherapy
No chemotherapy
Final pathology margin
Number of patients
Any local failure at 5 years (%)
Number of patients
Any local failure at 5 years (W)
p value*
Negative Positive Close Unknown
60 18 6 101
12 6 0 2
197 39 31 245
7 0 14 11
.96 .55 .18 .07
Overall
185
5
512
9
.09
* Mantel-Cox test (19).
285
Significance of the pathology margins 0 L. J. SOLIN el ul. Table 6. Review of series reporting breast recurrence as a function of the pathology margin of the tumor excision Crude breast recurrence (%) by pathology margin
5-year actuarial breast recurrence (%) by pathology margin Author
Total number of patients
Bartelink et al. (2) Clarke et al. (5) Fisher et al. (9) Hunig et al. (14) Kurtz et al. (17) Ryoo et al. (22) Schmidt-Ullrich et al. (23) Zafrani et al. (35) Solin et al. (present series)
Negative
Positive
Close
Unknown
Negative
Positive
Close
Unknown
585 362 569 105 496 393
2* 5* -
6* -
4* -
-
4 I 8 6
-
-
(
114 433
9’
2;+
-
-
0 8
0 25
697
I
2
11
I
5
* Estimated from curves.
In comparison to breast recurrence rates for patients with negative margins, three studies have found higher breast recurrence rates for patients with positive margins with crude breast recurrence rates of 13%-25% (17, 22, 35)
whereas three other studies have found no higher breast recurrence rates for patients with positive margins with crude breast recurrence rates of 0%-9% (5, 14,23). In the study of Kurtz et al. (17), analysis of the margins was performed retrospectively, and inking of the margins had not been performed. In the study of Zafrani et al. (35) margins were defined as positive on gross examination or on microscopic pathology examination. Fisher et al. (9) reported an g-year actuarial breast recurrence rate of 10% in patients with pathologically confirmed negative margins, and the patients in that study were treated with whole breast radiotherapy without a boost to the primary tumor site. In patients who have undergone complete gross excision of the primary tumor, there is a significant incidence of microscopically positive margins at the time of pathologic evaluation of the biopsy specimen. Fisher et al. (8) reported that 10% of 1257 patients treated by lumpectomy were found to have microscopically positive margins. Of the 63 1 patients in the present study treated with complete gross excision of the primary tumor at the time of initial excision (i.e., excluding initial incisional biopsies and excluding re-excisional biopsies), 13% (80/63 1) were found to have a positive margin on initial biopsy, and 4% (23/ 63 1) were found to have a close margin on initial biopsy. Other studies have also noted significant rates of microscopically positive margins after excisional biopsy of the primary tumor with an incidence of 9%-28% (2,5,8, 14, 18, 20, 29, 34). Patients with clinical T-2 lesions have been reported to have a positive margin of resection more frequently than patients with clinical T- 1 lesions (8, 14, 20). Schnitt et al. (24) found that the microscopic margins from the primary tumor excision were positive in 95% of the cases with EIC (extensive intraductal component) present as compared to 65% without EIC present. Al-
9
9 7 24 13
8 0
0
-
-
14
11
+At 10 years.
though the incidence of microscopically positive margins of resection decreases as the biopsy procedure progresses from lumpectomy to wide excision to quadrantectomy ( 11, 15, 34), this must be balanced against the ability of the radiation oncologist to obtain adequate local control in the presence of a focally microscopically positive or close margin as well as the possibility of less than optimal cosmesis with a wide excision or quadrantectomy. Re-excisional biopsy procedures have become more commonly used in an attempt to obtain pathologically confirmed negative margins of tumor resection. The incidence of residual tumor at the time of re-excisional biopsy has been found to be 32%-62% (20,2 1,24, 25,29). In a previous report by our group, the incidence of residual tumor on re-excisional biopsy was found to be 60% for patients with positive margins on initial excision and 49% for patients with unknown margins on initial excision (29). The incidence of positive re-excisions for patients with positive initial biopsy margins has been reported as being 55% by McCormick et al. (20) and 69% by Schnitt et al. (24). Frazier et al. (10) reported that there was residual tumor at the time of re-excision or mastectomy in 53% of patients with positive margins on initial biopsy. Two studies have found that the incidence of residual tumor for patients with an initially negative margin of resection was 33% as reported by Schnitt et al. (24) and 26% as reported by Frazier et al. (10). Other factors have been associated with high rates of residual carcinoma on re-excision. Solin et al. (29) reported that there was residual carcinoma on re-excision in 86% of patients who were found to have residual microcalcifications on a post-biopsy mammogram. Schnitt et al. (24) reported that patients with extensive intraductal component (EIC) on initial biopsy were found to have an 88% incidence of residual carcinoma at the time of re-excision. Factors which have been proposed as indications for a re-excisional biopsy prior to definitive breast irradiation include initial positive margins (20, 24, 29) initial unknown margins (29) residual microcalcifications on post-biopsy mammogram
286
I. J. Radiation Oncology 0 Biology 0 Physics
(29) the presence of extensive intraductal component (EIC) (24) and a biopsy elsewhere (i.e., outside of the treatment institution) (2 1, 25). In summary, the present study has demonstrated adequate local control and survival in selected patients with
July 1991. Volume 21. Number 2
the potentially high risk factors of positive or close microscopic pathology margins. Patient selection and the technical delivery of the radiotherapy including a boost may have been important contributing factors to the good outcome in these potentially high risk groups.
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