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Breast conservation therapy for intraductal carcinoma of the breast
0360-3016/93 $6.00 + .I0 copyright 0 1993 Pergamon Press Ltd.
IM J Radrarwn Oncoology RioI Phys, Vol. 26. pp. 39 l-396 Printed in the U.S.A. All nghts reserved.
??Clinical Original Contribution
BREAST
CONSERVATION
ROBERT
R. KUSKE, CARLOS GORDON
M.D.,’
THERAPY FOR INTRADUCTAL OF THE BREAST JOSEPH
A. PEREZ, PHILPOTT,
M.
M.D.,’ M.D.3
BEAN,
B.A.,2
DOROTHY
DELIA
ANDRIOLE,
AND BARBARA
CARCINOMA
M. GARCIA,
M.D.,’
M.D.,3
FINEBERG,
B.A.’
‘Radiation Oncology Center, Mallinckrodt Institute of Radiology and 3Department of Surgery, Washington University Medical Center, St. Louis, MO 63110; and ‘Washington University School of Medicine, St. Louis, MO 63 1 10 Purpose: Between 1979 and 1987, 76 women with 77 ductal carcinomas in-situ of the breast were evaluated by TheRadiation Oncology Center after breast conservation surgery. Methods and Materials: Seventy breasts (91%) had tylectomy and irradiation and seven breasts (9%) had tylectomy alone. Median follow-up was 4.0 years, with a range of 2-10 years. Fifty patients (65%) had occult lesions discovered by mammography with a median mammographic size of 0.9 cm. The twenty-six patients with presenting symptoms had a median clinical tumor size of 1.95 cm. All patients had local excision of the primary tumor. Of 15 patients who had axillary dissections, one had nodal metastasis. Seventy breasts were irradiated. Seven patients refused radiotherapy. Results: Overall 5-year actuarial survival was 99%; 5-year actuarial disease-free survival was 89%; the 5-year -1 intramammary tumor control rate for irradiated patients was 93% vs. 57% for patients not irradiated (p < 0.001). Comedocarcinoma had a 5-year actuarial tumor control rate of 75%, 88% in the irradiated group as compared to 98% for all other histologic subtypes of ductal carcinoma in situ (p < 0.03). All six patients with local failure were successfully salvaged by further surgery. Multivariate analysis revealed significant factors in local control to be (a) radiotherapy, (b) comedocarcinoma histology, and (c) menopausal status. Conclusions: Although the number of patients treated is small, and follow-up time is limited, these early results support the contention that the treatment of ductal carcinoma in situ by excision and irradiation is an acceptable alternative to mastectomy. We urge caution in treating patients with the comedocarcinoma subtype and counsel these patients to have more treatment than excision alone. Breast cancer, Intraductal breast cancer, Noninvasive Radiotherapy, Breast conservation.
breast cancer, Ductal carcinoma in situ, Comedocarcinoma,
considered a valid alternative to mastectomy (1, 2, 6-9, 11, 12, 14, 17-23, 25). Since acceptance of screening mammography is a recent phenomenon, there is less clinical experience with a breast-conserving approach for in situ than for invasive breast carcinoma. This report describes the outcome of breast conservation therapy for DCIS evaluated at the Radiation Oncology Center with emphasis on prognostic factors.
INTRODUCIION Intraductal breast cancer, or ductal carcinoma in situ (DCIS) is defined as breast cancer confined to the ducts of the breast without light microscopy evidence of penetration of the basement membrane (5). At Washington University Medical Center (WUMC), DCIS accounted for less than 5% of all breast cancers prior to 1980 compared to 20% in 1990. The widespread use of screening mammography, as well as public and physician awareness of the value of early breast cancer detection, has dramatically increased the number of non-invasive breast cancers detected. The traditional treatment for noninvasive ductal carcinoma has been a total mastectomy, with or without a simultaneous limited axillary dissection. For appropriately selected patients, however, conservative treatment is now
METHODS
AND
MATERIALS
Between 1979 and 1987, 76 women with DCIS were treated by conservation surgery with or without irradiation at Washington University Medical Center (WUMC). All patients had radiation oncology consultations. Since one patient had bilateral DCIS, 77 intraductal breast cancers
Center for Radiation Oncology, The Ochsner Clinic, 1516 Jefferson Highway, New Orleans, LA 70 12 1. Accepted for publication 30 December 1992.
Presented at the 33rd Meeting of the American Society for Therapeutic Radiology and Oncology, Washington, D. C., November 199 1. Reprint requests to: Robert R. Kuske, M.D., The Ochsner 391
1. J. Radiation Oncology
392
0 Biology 0 Physics
Table 1. lntraductal carcinoma of the breast: Patient characteristics
Age: Race: Menopausal
status:
Family history of breast cancer: Presenting patients
symptoms: [35%])
(26
Follow-up:
Median 55 years Range: 34-84 years Black 20% White 80% Premenopausal 34% Postmenopausal 58% Unknown 8% Positive 26% Negative 74% Mass (70%) Pain ( 15%) Nipple discharge (7.4%) Median 4.0 years Range: 2- 10 years
were included in this analysis. Patient characteristics are listed in Table 1. All patients had pathologically confirmed DCIS without evidence of an invasive component. Eightynine percent of these patients had mammography, with a median mammographic tumor size of 1.5 cm (range 0.8-6.0 cm). The median clinical tumor size for these patients was 1.95 cm (Table 2). All patients had an excisional biopsy of the tumor. The status of microscopic margins was determined in only 2 l/ 77 (27%) of these biopsies. Results and subsequent therapy are summarized in Table 3. Tumor size was measured pathologically in 30 patients; the median size was 0.7 cm. (range 0.2-3.0 cm). The distribution of histologic types of DCIS is illustrated in Table 4. Fifteen patients had a limited staging axillary dissection and five of these patients had clinically palpable nodes. Only one patient in the group with clinically positive nodes had documented nodal metastasis; confirmation of this diagnosis was made by two pathologists who independently reviewed the specimen. The remaining 14 axillary dissections were negative. Table 2. lntraductal
carcinoma of the breast: Median clinical
size vs. median
mammographic Median
Median
clinical size (cm)
Clinically symptomatic N = 27 (35%) 1.95 (range 0.00-4.00) Clinically occult N = 50 (65%) N/A Mammographic findings: Microcalcifications only Mass only Microcalcifications + Mass
* Vax 8600.
size mammographic size (cm)
Volume
26, Number 3, 1993
Table 3. Ductal carcinoma in situ (DCIS) of the breast: Surgical margins
Margins
Pts.
Positive* Negative Indeterminate+ Not assessed
2 16 3 56
No. with DCIS at reexcision
No. re-excised 2 0 1 17
Local recurrence
2 0 0 I1
0 1 0 2
* Positive margins had malignant cells at the inked edge. + Specimen was not coated with India ink and margins could not be reliably assessed.
Radiation therapy was delivered with 4-6 MV X rays by tangential fields encompassing the entire breast to tumor doses of 50 Gy. Fifty-seven patients had a boost to the tumor bed, 54 with 9-l 2 MeV electrons, and three with interstitial implants. Median total dose to the tumor bed was 56.8 Gy in 1.8-2 Gy daily fractions. Seven patients refused radiotherapy following local excision, Median mammographic size for this group was 1.0 cm (0.5-2.8 cm). Six of these patients had clinically occult (mammographically detected) tumors, and one presented with serous nipple discharge and was found to have an abnormal mammogram. This study was analyzed on a mainframe computer* using BMDP statistical software (3). Actuarial local recurrence rates were calculated by the life table method, and statistics provided are those developed by Mantel and Cox. Multivariate analysis was performed using the method developed by Cox. RESULTS
Three of the 70 patients (4.3%) who had local excision and radiotherapy developed a recurrence in the treated breast. Of the seven patients treated with excision-alone, three (43%) developed local recurrence. In addition, one patient died of widely metastatic breast carcinoma; this patient had been treated with a modified radical mastectomy for invasive cancer of the contralateral breast 2 years previous to her diagnosis of DCIS. Actuarial 5-year survival was 99% (Table 5). Five year actuarial disease-free Table 4. Intraductal carcinoma of the breast: Histologic subtype
1.50 (range 0.80-6.00) Number 0.90 (range 0.30-4.20) All patients 60% 15% 25%
Comedocarcinoma Cribriform Papillary Micro papillary Not specified
27 24 5 3 18
(%) (35) (31) (7) (4) (23)
Breast conservation for DCIS 0 R. R. KLJSKEet al. Table 5. Intraductal
carcinoma
of the breast: 5-year actuarial
survivals and intramammary
Survival %
Overall
77
99
Disease-free
77
89
No. Intramammary XRT No XRT
control
Comedo Other paths Menopausal
Pre Post
survival was 89%. Patients undergoing excision plus radiation had an actuarial 5-year local tumor control rate of 93%, compared to 57% in the group who had excision only (Fig. 1). Characteristics of the six patients who failed locally are outlined in Table 6. All three of the local recurrences after irradiation were comedocarcinoma, and two excisionalone patients with local failure were also comedocarcinoma (Fig. 2). The other local failure in the excision alone group was originally not classified histologically, although the local recurrence was pathologically the cribriform subtype. Whether the patient’s disease was symptomatic or occult at diagnosis did not influence intramammary control. All six local failures have been surgically salvaged and all patients remain locally controlled and free of disease. Four patients had mastectomy for local recurrence, one had a wide local excision followed by radiotherapy, and one was treated with wide local excision alone. Factors affecting local control on multivariate analysis
alone (n=7)
P<0.0001
0
’
i
I
I
I
I
1
2
3
4
5
TIME (years)
Fig. 1. Intramammary vs. excision
alone.
control by radiation
control
rates
Intramammary
No.
Surgery
393
therapy plus excision
control %
77 70 7
90 93 p < 0.001 57
27 50
75 p < 0.03 98
26 45
79 p < 0.3 93
status
were radiotherapy, comedocarcinoma histology, and premenopausal status. Given the small range of doses applied, no irradiation dose-response relationship was found. Because of the limited number of surgical margins evaluated, the impact of positive surgical margins could not be assessed. Only one failure occurred in the group of patients whose margins were evaluated, and this patient had negative margins (Table 3). The other breast failures occurred in patients whose margins were not evaluated. Cosmetic results were good or excellent in 85% of the patients, using our established criteria for breast conservation treatment (Table 7). Three irradiated patients (4%) experienced treatment sequelae, including a post-implant wound infection, symptomatic breast fibrosis, and diffuse skin blistering in a patient treated with bolus. DISCUSSION With increasing numbers of patients opting for breast conservation as local therapy after diagnosis of invasive ductal carcinoma, denying this option to women with the earliest, non-invasive stage of breast cancer is difficult to justify. Our clinical results with tumor excision followed by irradiation are comparable to other reported series. Considering the long natural history of in situ breast cancer, a median follow-up of 4 years is not conclusive, but is in line with many other published studies (1, 2, 7-9, 17,22,23). The crude incidence of recurrence ranges from 4% to 11% in published reports of conservative surgery and irradiation, but more accurate actuarial breast tumor recurrence rates of 6-27% at 5 to 10 years have been reported ( 1, 1S), emphasizing the importance of careful longterm follow-up in these patients. Sixty-five percent of the patients in our study presented with non-palpable, mammographically discovered lesions, significantly different from studies prior to 1986, in which percentages of patients with palpable lesions ranged as high as 100%. Page et al. (15) noted palpable lesions in 100% of their patients in a study from 1982, and Fisher et al. (5) found palpable lesions in 100% in 1985. It is possible that palpable intraductal breast cancer is a different clinical entity than occult non-invasive breast can-
394
1. J. Radiation Oncology 0 Biology 0 Physics Table 6. Ductal carcinoma
Volume 26, Number 3, 1993
in situ (DCIS) of the breast: Intramammary Patient
1
2
0
XRT (cGY) DCIS Subtype Histology of recur. Age Nipple discharge Clinical presentat’n Clinical stage* Months to recur. Treat. of recur. Salvage Mos. since salvage
0
NOS Cribrif. 37 -
Comedo NOS
Sympt TX 13 WLE NED 78
Sympt Tl
35 _
26 MRM + reconstruction NED 71
no. 4
3 6240 Comedo Invas. 42 _
5690 Comedo Invas. 59 _
Occult Tl 15 MRM NED 31
Occult Tl 31 MRM NED 9
NOS = Not otherwise specified; * Clinical stage is based upon the palpable or mammographic local excision; MRM = Modified radical mastectomy; NED = No evidence of disease.
cer; the failure rate has been reported as greater for palpable than radiographically detected in situ cancers (7). In our study, the pathologic size of mammographically detected lesions was 0.9 cm, as compared to 1.95 cm for symptomatic patients. Despite this apparent difference in tumor burden, there was no difference in the rate of local failure between these subsets of patients. All patients were treated with local excision of all gross tumor. Surgical margins of only 2 l/77 (30%) of specimens were assessed pathologically and only one local failure occurred in this group. Five local failures occurred in patients whose surgical margins were not evaluated pathologically. It is possible that some patients whose margins were not evaluated had a substantial number of clonogenic malignant cells remaining in the breast, which could not
80 6
Comedo(n=27)
F 5 0
60 PcO.03
a
failure
5 0
Comedo Invas. 52 + Occult Tl 23 WLE + RT NED 25
6 6040 Comedo Invas. 40 _ Occult T2 53 MRM NED 4
size of the lesion; WLE = Wide
be controlled with conventional doses of irradiation. McCormick et al. ( 12) reported that 30% of their patients with local recurrence had close or involved margins and only 4% of locally controlled patients had positive/close margins. Careful attention to surgical margins through routinely blotting the surface of the specimen with India ink prior to sectioning and orienting the specimen, is recommended in breast conservation therapy for intraductal breast cancer (6, 7). Within the past decade, there has been a trend towards the elimination of axillary dissections in patients with intraductal breast cancer because of the extremely low incidence of metastasis. Fisher et al. (5,6) found no positive nodes in 78 patients registered in the National Surgical Adjuvant Breast Project (NSABP) protocol B-06. In NSABP Protocol B 17, an axillary dissection was initially required, but this stipulation was dropped in the midst of patient accrual because of preliminary results. Recently Silverstein et al. (2 1) reported one of 183 patients (0.5%) with a positive axillary dissection. We do not recommend axillary dissection unless the nodes are palpable, or the mammographic extent ofthe intraductal carcinoma is diffuse (greater than 4 cm), increasing the odds of a sampling error for microinvasive or frankly invasive cancer (10, 11). Irradiation of the regional lymph nodes, as reported by Zafrani (25) in some patients, is also not necessary. Seventy of 77 breasts (9 1%) in this study were irradiated. Table 7. Intraductal Cosmesis
carcinoma of the breast: scoring criteria
20
0-
1
1
I
I
I
I
1
2
3
4
TIME
(years)
Fig. 2. Intramammary control by histology-Comedocarcinoma vs. other histologic subtypes of ductal carcinoma in situ.
1 5
Excellent: Minimal or no difference in the size, shape, or texture; Slight thickening or scar tissue permissable Good: Mild asymmetry; Slight reddening or darkening of the breast; Some thickening or scar tissue Fair: Obvious difference in the size, shape, and texture; Moderate thickening or scar tissue; Obvious color changes Poor: Marked change in the appearance, involving more than a of the breast tissue; Obvious skin changes; Severe scarring and thickening
Breast conservation for DCIS 0 R. R. KUSKE et
The importance of radiotherapy to the intact breast following wide local excision is a source of considerable debate and investigation in the recent literature. This issue is the focus of NSABP Protocol B 17, which closed in December 1990; results will not be available until the data matures. In our analysis, irradiated patients had fewer local failures than those in the excision alone group, but the small number (7) in the excision-alone group makes us reluctant to draw conclusions despite the statistical significance. Patients refusing radiation did not have worse prognostic indicators. Pathologic size, percentage of comedocarcinoma histology, clinical features, and surgical factors were comparable between the two groups. With excision-alone, multicentricity is a major concern. According to Lagios (lo), 54% of intraductal carcinomas larger than 2.5 cm were multicentric. In our study, 6 of 7 breasts (86%) treated with excision alone had a tumor size less than or equal to 2.5 cm, which yields an increase of multicentricity of only 14%. The fact that all of the comedocarcinomas in the unirradiated group versus 3/25 ( 12%) of the irradiated group experienced local failure suggests that this histologic subtype may not be suitable for local excision alone. Further, all three of our local recurrences following irradiation were comedocarcinoma, lending credence to the hypothesis that this histologic subtype may be more biologically aggressive. Silverstein et al. (2 1) noted an 11% incidence of local recurrence in 53 patients treated with local excision and irradiation of comedocarcinoma compared with 2% (l/5 1) of other types of DCIS treated with breast conservation. In contrast, Bornstein et al. (1) observed a 22% incidence of local recurrence (6/27) in patients with comedocarcinoma vs. 20% (2/ 10) in those with other subtypes, all treated by excision and irradiation. Lagios et al. (11) treated patients selected according to strict criteria with wide excision alone between 1972 and 1987. The recurrence rate was 19% (7/36) in patients with comedocarcinema or cribriform with necrosis in contrast to 0 of 33 patients with a micropapillary histology and l/ 10 ( 10%) with cribriform with anaplasia (Q = 0.028). It should be emphasized that histologic patterns are frequently diverse, and that our study and others report the predominant patsubtype. Fisher et al. (5) found pure or predominant terns in only 6-2 1%. Zafrani et al. (25) found more than one subtype in 48%. One possible explanation of these findings is that comedocarcinoma has a higher proliferative index compared to other histologic subtypes, leading to earlier recurrence and accounting for a higher failure rate early in the study. It is possible that the local failure rate of other histologic subtypes will ‘catch up’ when current studies achieve 10 to 15 year follow-up. Meyer (13) noted that comedocarcinema had a significantly higher thymidine labeling index and S-phase fraction, compared to other histologic subtypes. Van der Vijver et al. (24) reported that solid and comedo subtypes of DCIS over express the neu-protein as compared to small-cell, papillary, or cribriform types.
al.
395
Fentiman et al. (4) and Patchefsky et al. (16) noted relatively greater numbers of mitoses and increased cellular pleomorphism in comedocarcinoma, and more diffuse extension of this DCIS subtype in the excision specimen. However, Patchefsky et al. (16) found no multicentricity within the comedo subtype, compared to 80% for micropapillary, 36% for papillary, and 27% for solid/cribiform. Further, they concluded that small nonpalpable cribriform histologies should be treated by wide local excision alone, without breast irradiation, and recommended irradiation for micropapillary and papillary subtypes because of a greater incidence of multicentricity. Fentiman et al. (4) found 23% of comedo specimens multicentric and approximately the same percentage of multicentricity in all other subtypes. All six intramammary failures in our series were successfully salvaged with further surgery (Table 6). Of concern, however, is that four of the six local recurrences (67%) were invasive carcinoma. This finding of approximately 50% invasive carcinomas in intramammary recurrences is similar to other series (21). Patients failing with invasive carcinoma are at risk for distant failure with continued follow-up, but the rate of distant failure in the studies published to date show no significant difference between patients treated with mastectomy and conservation therapy (2, 8, 9, 14-16). Close surveillance after treatment is critical, since early detection of the 7% to 10% who may fail by 5 years will allow optimal salvage surgery for cure. We see our patients as a team every 3 months for the first year, every 4 months for the second year, and every 6 months thereafter. Ipsilateral mammograms are performed at 6-month intervals from the completion of irradiation for the first 2 years, then yearly. Patients treated with breast conservation therapy for intraductal breast cancer as an alternative to mastectomy will still have breast tissue at risk of developing breast cancer. This risk may be higher with comedocarcinoma especially if the breast is not irradiated. However, as long as salvage surgery proves successful and the overall survival rates are comparable to those after initial mastectomy, many patients will continue to choose breast conservation therapy as local treatment for DCIS as well as invasive ductal cancer. In our study, quality of life in patients undergoing conservation surgery and irradiation was excellent, with an 85% excellent/good cosmesis rate, and minimal complications. Every patient stated retrospectively that she would choose conservation therapy again (the four patients treated with modified radical mastectomy for intramammary recurrences were not questioned after surgery). Further studies with larger numbers of patients and long term follow-up are required to address the issues raised by these data. Criteria for inclusion in such studies should be carefully defined and perhaps broadened, since, as noted by Fentiman et al. (4) in an EORTC trial, only 77 of 2 16 (36%) eligible patients were actually entered in this study.
396
1. .I. Radiation Oncology 0 Biology 0 Physics
Questions remain. Will a significantly higher percentage of irradiated patients retain their breast at 10 years compared with patients treated with excision alone, because of a decrease in the rate of local recurrence? Does comedocarcinoma histology contraindicate local excision alone,
Volume 26, Number 3, 1993
or even local excision and irradiation? Will pathologic assessment of surgical margins aid in selecting patients? And will the overall survival rate at 10, 1.5, or 20 years be comparable to that of patients treated with mastectomy?
REFERENCES 1. Bornstein, B. A.; Recht, A.; Connolly, J. L.; Schnitt, S. J.; Cady, B.; Koufman, C.; Love, S.; Osteen, R. T.; Harris, J. R. Results of treating ductal carcinoma in situ of the breast with conservative surgery and radiation therapy. Cancer 67:7-13;1991. 2. Delouche, G.; Bachelot, F.; Premont, M.; Kurtz, J. M. Conservation treatment of early breast cancer: Long term results and complications. Int. J. Radiat. Oncol. Biol. Phys. 13:2934;1987. 3. Dixon, W. J., ed. BMDP statistical software manuals, Vol. 1 and Vol. 2. Berkeley, CA: University of California Press; 1989. 4. Fentiman, J. P.; Julien, J. P.; van Dongen, J. A.; van Gell, B.; Chetty, U.; Coibion, M. Reasons for non-entry of patients with DCIS of the breast into a randomized trial (EORTC 10853). Cancer 27:450-452; 199 1. 5. Fisher, E. R.; Sass, R.; Fisher, B.; Wickerham, L.; Paik, S. M. Collaborating NSABP Investigators. Pathologic findings from the National Surgical Adjuvant Breast Project (Protocol 6): Intraductal carcinoma (DCIS). Cancer 57: 197208;1986. 6. Fisher, E. R.; Leeming, R.; Anderson, S.; Redmond, C.; Fisher, B. Collaborating NSABP Investigators. Conservative management of intraductal carcinoma (DCIS) ofthe breast. J. Surg. Oncol. 47:139-147;1991. 7. Fowble, B. Intraductal noninvasive breast cancer: A comparison of three local treatments. Oncology 3(6):5 l-58; 1989. D.; Pathare, P. 8. Haffty, B. G.; Peschel, R. E.; Papadopoulos, Radiation therapy for ductal carcinoma in situ ofthe breast. Conn. Med. 54(9):482-484; 1990. J.; Torhorst, J.; Spitalier, J.; 9. Kurtz, J. M.; Jacquemier, Amalric, R.; Hunig, R.; Walther, E.; Harder, F.; Almendral, A.; Brandone, H.; Ayme, Y.; Roth, J. Conservation therapy for breast cancers other than infiltrating ductal carcinoma. Cancer 63:1630-1635;1989. 10. Lagios, M. D.; Westdahl, P. R.; Margolin, F. R.; Rose, M. R. Duct carcinoma in situ: Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer 50: 1309- 13 14; 1982. Il. Lagios, M. D.; Margolin, F. R.; Westdahl, P. R.; Rose, M. R. Mammographically detected duct carcinoma in situ: Frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer 63:618-624;1989. 12. McCormick, B.; Rosen, P. P.; Kinne, D.; Cox, L.; Yaholom, J. Duct carcinoma in situ of the breast: An analysis of local control after conservation surgery and radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2 1(2):289-292;199 1. 13. Meyer, J. S. Cell kinetics of histologic variants of in situ breast carcinoma. Breast Cancer Res. Treat. 17 1- 180; 1986.
14. Millis, R. R.; Thynne, G. S. J. In situ intraduct carcinoma of the breast: A long term follow-up study. Br. J. Surg. 62:957-62; 1975. 15. Page, D. L.; DuPont, W. D.; Rogers, L. W.; Landenberger, M. Intraductal carcinoma of the breast: Follow-up after biopsy only. Cancer 49:751-758;1982. 16. Patchefsky, A. S.; Schwartz, G. F.; Finkelstein, S. D.; Prestipino, A.; Sohn, S. E.; Singer, J. S.; Feig, S. A. Heterogeneity of intraductal carcinoma of the breast. Cancer 63:731741;1989. 17. Recht, A.; Donoff, S.; 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(10):1339-1343;1985. 18. Recht, A.; Solin, L. J.; Kurtz, J. M.; Cross, M. A.; Kuske, R. R.; McCormick, B.; McNeese, M.; Harris, J. R.; Fowble, R. L. Conservative surgery and radiotherapy (CS & RT) for ductal carcinoma in situ (DCIS) (Abstract). Program/Proceedings Amer. Sot. Clin. Oncol. 10:47; 199 1. 19. Rosner, D.; Bedwani, R. N.; Vana, J.; Baker, H. W.; Murphy, G. P. Noninvasive breast carcinoma: Results of a national survey by the American College of Surgeons. Ann. Surg. 192:139-147;1980. 20. Schnitt, S. J.; Silen, W.; Sadowsky, N. L.; Connolly, J. L.; Harris, J. R. Ductal carcinoma in situ (intraductal carcinoma) ofthe breast. N. Eng. J. Med. 318( 14):898-903;1988. 21. Silverstein, M. J.; Waisman, J. R.; Gamagami, P.; Gierson, E. D.; Colbum, W. J.; Rosser, R. J.; Gordon, P. S.; Lewinsky, B. S.; Fingerhut, A. Intraductal carcinoma of the breast (208 cases): Clinical factors influencing treatment choice. Cancer 66:102-108;1990. 22. Solin, L. J.; Fowble, B. L.; Schultz, D. J.; Yeh, I.; Kowalyshyn, M. J.; Goodman, R. L. Definitive irradiation for intraductal carcinoma of the breast. Int. J. Radiat. Oncol. Biol. Phys. 19:843-850;1990. 23. Stotter, A. T.; McNeese, M.; Oswald, M. J.; Ames, F. C.; Romsdahl, M. M. The role of limited surgery with irradiation in primary treatment of ductal in situ breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 19:283-287;1990. 24. Van de Vijver, M. J.; Peterse, J. L.; Moor, W. J.; Wisman, P.; Lomaus, J.; Dalesio, 0.; Nusse, R. Nets-protein overexpression in breast cancer: Association with comedo-type ductal carcinoma in situ and limited prognostic value in Stage II breast cancer. N. Eng. J. Med. 3 19( 19): 123945;1988. 25. Zafrani, B.; Fourquet, A.; Vilcoq, J. R.; Legal, M.; Calle, R. Conservative management of intraductal breast carcinoma with tumorectomy and radiation therapy. Cancer 57: 1299-1301;1986.
IM J Radrarwn Oncoology RioI Phys, Vol. 26. pp. 39 l-396 Printed in the U.S.A. All nghts reserved.
??Clinical Original Contribution
BREAST
CONSERVATION
ROBERT
R. KUSKE, CARLOS GORDON
M.D.,’
THERAPY FOR INTRADUCTAL OF THE BREAST JOSEPH
A. PEREZ, PHILPOTT,
M.
M.D.,’ M.D.3
BEAN,
B.A.,2
DOROTHY
DELIA
ANDRIOLE,
AND BARBARA
CARCINOMA
M. GARCIA,
M.D.,’
M.D.,3
FINEBERG,
B.A.’
‘Radiation Oncology Center, Mallinckrodt Institute of Radiology and 3Department of Surgery, Washington University Medical Center, St. Louis, MO 63110; and ‘Washington University School of Medicine, St. Louis, MO 63 1 10 Purpose: Between 1979 and 1987, 76 women with 77 ductal carcinomas in-situ of the breast were evaluated by TheRadiation Oncology Center after breast conservation surgery. Methods and Materials: Seventy breasts (91%) had tylectomy and irradiation and seven breasts (9%) had tylectomy alone. Median follow-up was 4.0 years, with a range of 2-10 years. Fifty patients (65%) had occult lesions discovered by mammography with a median mammographic size of 0.9 cm. The twenty-six patients with presenting symptoms had a median clinical tumor size of 1.95 cm. All patients had local excision of the primary tumor. Of 15 patients who had axillary dissections, one had nodal metastasis. Seventy breasts were irradiated. Seven patients refused radiotherapy. Results: Overall 5-year actuarial survival was 99%; 5-year actuarial disease-free survival was 89%; the 5-year -1 intramammary tumor control rate for irradiated patients was 93% vs. 57% for patients not irradiated (p < 0.001). Comedocarcinoma had a 5-year actuarial tumor control rate of 75%, 88% in the irradiated group as compared to 98% for all other histologic subtypes of ductal carcinoma in situ (p < 0.03). All six patients with local failure were successfully salvaged by further surgery. Multivariate analysis revealed significant factors in local control to be (a) radiotherapy, (b) comedocarcinoma histology, and (c) menopausal status. Conclusions: Although the number of patients treated is small, and follow-up time is limited, these early results support the contention that the treatment of ductal carcinoma in situ by excision and irradiation is an acceptable alternative to mastectomy. We urge caution in treating patients with the comedocarcinoma subtype and counsel these patients to have more treatment than excision alone. Breast cancer, Intraductal breast cancer, Noninvasive Radiotherapy, Breast conservation.
breast cancer, Ductal carcinoma in situ, Comedocarcinoma,
considered a valid alternative to mastectomy (1, 2, 6-9, 11, 12, 14, 17-23, 25). Since acceptance of screening mammography is a recent phenomenon, there is less clinical experience with a breast-conserving approach for in situ than for invasive breast carcinoma. This report describes the outcome of breast conservation therapy for DCIS evaluated at the Radiation Oncology Center with emphasis on prognostic factors.
INTRODUCIION Intraductal breast cancer, or ductal carcinoma in situ (DCIS) is defined as breast cancer confined to the ducts of the breast without light microscopy evidence of penetration of the basement membrane (5). At Washington University Medical Center (WUMC), DCIS accounted for less than 5% of all breast cancers prior to 1980 compared to 20% in 1990. The widespread use of screening mammography, as well as public and physician awareness of the value of early breast cancer detection, has dramatically increased the number of non-invasive breast cancers detected. The traditional treatment for noninvasive ductal carcinoma has been a total mastectomy, with or without a simultaneous limited axillary dissection. For appropriately selected patients, however, conservative treatment is now
METHODS
AND
MATERIALS
Between 1979 and 1987, 76 women with DCIS were treated by conservation surgery with or without irradiation at Washington University Medical Center (WUMC). All patients had radiation oncology consultations. Since one patient had bilateral DCIS, 77 intraductal breast cancers
Center for Radiation Oncology, The Ochsner Clinic, 1516 Jefferson Highway, New Orleans, LA 70 12 1. Accepted for publication 30 December 1992.
Presented at the 33rd Meeting of the American Society for Therapeutic Radiology and Oncology, Washington, D. C., November 199 1. Reprint requests to: Robert R. Kuske, M.D., The Ochsner 391
1. J. Radiation Oncology
392
0 Biology 0 Physics
Table 1. lntraductal carcinoma of the breast: Patient characteristics
Age: Race: Menopausal
status:
Family history of breast cancer: Presenting patients
symptoms: [35%])
(26
Follow-up:
Median 55 years Range: 34-84 years Black 20% White 80% Premenopausal 34% Postmenopausal 58% Unknown 8% Positive 26% Negative 74% Mass (70%) Pain ( 15%) Nipple discharge (7.4%) Median 4.0 years Range: 2- 10 years
were included in this analysis. Patient characteristics are listed in Table 1. All patients had pathologically confirmed DCIS without evidence of an invasive component. Eightynine percent of these patients had mammography, with a median mammographic tumor size of 1.5 cm (range 0.8-6.0 cm). The median clinical tumor size for these patients was 1.95 cm (Table 2). All patients had an excisional biopsy of the tumor. The status of microscopic margins was determined in only 2 l/ 77 (27%) of these biopsies. Results and subsequent therapy are summarized in Table 3. Tumor size was measured pathologically in 30 patients; the median size was 0.7 cm. (range 0.2-3.0 cm). The distribution of histologic types of DCIS is illustrated in Table 4. Fifteen patients had a limited staging axillary dissection and five of these patients had clinically palpable nodes. Only one patient in the group with clinically positive nodes had documented nodal metastasis; confirmation of this diagnosis was made by two pathologists who independently reviewed the specimen. The remaining 14 axillary dissections were negative. Table 2. lntraductal
carcinoma of the breast: Median clinical
size vs. median
mammographic Median
Median
clinical size (cm)
Clinically symptomatic N = 27 (35%) 1.95 (range 0.00-4.00) Clinically occult N = 50 (65%) N/A Mammographic findings: Microcalcifications only Mass only Microcalcifications + Mass
* Vax 8600.
size mammographic size (cm)
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26, Number 3, 1993
Table 3. Ductal carcinoma in situ (DCIS) of the breast: Surgical margins
Margins
Pts.
Positive* Negative Indeterminate+ Not assessed
2 16 3 56
No. with DCIS at reexcision
No. re-excised 2 0 1 17
Local recurrence
2 0 0 I1
0 1 0 2
* Positive margins had malignant cells at the inked edge. + Specimen was not coated with India ink and margins could not be reliably assessed.
Radiation therapy was delivered with 4-6 MV X rays by tangential fields encompassing the entire breast to tumor doses of 50 Gy. Fifty-seven patients had a boost to the tumor bed, 54 with 9-l 2 MeV electrons, and three with interstitial implants. Median total dose to the tumor bed was 56.8 Gy in 1.8-2 Gy daily fractions. Seven patients refused radiotherapy following local excision, Median mammographic size for this group was 1.0 cm (0.5-2.8 cm). Six of these patients had clinically occult (mammographically detected) tumors, and one presented with serous nipple discharge and was found to have an abnormal mammogram. This study was analyzed on a mainframe computer* using BMDP statistical software (3). Actuarial local recurrence rates were calculated by the life table method, and statistics provided are those developed by Mantel and Cox. Multivariate analysis was performed using the method developed by Cox. RESULTS
Three of the 70 patients (4.3%) who had local excision and radiotherapy developed a recurrence in the treated breast. Of the seven patients treated with excision-alone, three (43%) developed local recurrence. In addition, one patient died of widely metastatic breast carcinoma; this patient had been treated with a modified radical mastectomy for invasive cancer of the contralateral breast 2 years previous to her diagnosis of DCIS. Actuarial 5-year survival was 99% (Table 5). Five year actuarial disease-free Table 4. Intraductal carcinoma of the breast: Histologic subtype
1.50 (range 0.80-6.00) Number 0.90 (range 0.30-4.20) All patients 60% 15% 25%
Comedocarcinoma Cribriform Papillary Micro papillary Not specified
27 24 5 3 18
(%) (35) (31) (7) (4) (23)
Breast conservation for DCIS 0 R. R. KLJSKEet al. Table 5. Intraductal
carcinoma
of the breast: 5-year actuarial
survivals and intramammary
Survival %
Overall
77
99
Disease-free
77
89
No. Intramammary XRT No XRT
control
Comedo Other paths Menopausal
Pre Post
survival was 89%. Patients undergoing excision plus radiation had an actuarial 5-year local tumor control rate of 93%, compared to 57% in the group who had excision only (Fig. 1). Characteristics of the six patients who failed locally are outlined in Table 6. All three of the local recurrences after irradiation were comedocarcinoma, and two excisionalone patients with local failure were also comedocarcinoma (Fig. 2). The other local failure in the excision alone group was originally not classified histologically, although the local recurrence was pathologically the cribriform subtype. Whether the patient’s disease was symptomatic or occult at diagnosis did not influence intramammary control. All six local failures have been surgically salvaged and all patients remain locally controlled and free of disease. Four patients had mastectomy for local recurrence, one had a wide local excision followed by radiotherapy, and one was treated with wide local excision alone. Factors affecting local control on multivariate analysis
alone (n=7)
P<0.0001
0
’
i
I
I
I
I
1
2
3
4
5
TIME (years)
Fig. 1. Intramammary vs. excision
alone.
control by radiation
control
rates
Intramammary
No.
Surgery
393
therapy plus excision
control %
77 70 7
90 93 p < 0.001 57
27 50
75 p < 0.03 98
26 45
79 p < 0.3 93
status
were radiotherapy, comedocarcinoma histology, and premenopausal status. Given the small range of doses applied, no irradiation dose-response relationship was found. Because of the limited number of surgical margins evaluated, the impact of positive surgical margins could not be assessed. Only one failure occurred in the group of patients whose margins were evaluated, and this patient had negative margins (Table 3). The other breast failures occurred in patients whose margins were not evaluated. Cosmetic results were good or excellent in 85% of the patients, using our established criteria for breast conservation treatment (Table 7). Three irradiated patients (4%) experienced treatment sequelae, including a post-implant wound infection, symptomatic breast fibrosis, and diffuse skin blistering in a patient treated with bolus. DISCUSSION With increasing numbers of patients opting for breast conservation as local therapy after diagnosis of invasive ductal carcinoma, denying this option to women with the earliest, non-invasive stage of breast cancer is difficult to justify. Our clinical results with tumor excision followed by irradiation are comparable to other reported series. Considering the long natural history of in situ breast cancer, a median follow-up of 4 years is not conclusive, but is in line with many other published studies (1, 2, 7-9, 17,22,23). The crude incidence of recurrence ranges from 4% to 11% in published reports of conservative surgery and irradiation, but more accurate actuarial breast tumor recurrence rates of 6-27% at 5 to 10 years have been reported ( 1, 1S), emphasizing the importance of careful longterm follow-up in these patients. Sixty-five percent of the patients in our study presented with non-palpable, mammographically discovered lesions, significantly different from studies prior to 1986, in which percentages of patients with palpable lesions ranged as high as 100%. Page et al. (15) noted palpable lesions in 100% of their patients in a study from 1982, and Fisher et al. (5) found palpable lesions in 100% in 1985. It is possible that palpable intraductal breast cancer is a different clinical entity than occult non-invasive breast can-
394
1. J. Radiation Oncology 0 Biology 0 Physics Table 6. Ductal carcinoma
Volume 26, Number 3, 1993
in situ (DCIS) of the breast: Intramammary Patient
1
2
0
XRT (cGY) DCIS Subtype Histology of recur. Age Nipple discharge Clinical presentat’n Clinical stage* Months to recur. Treat. of recur. Salvage Mos. since salvage
0
NOS Cribrif. 37 -
Comedo NOS
Sympt TX 13 WLE NED 78
Sympt Tl
35 _
26 MRM + reconstruction NED 71
no. 4
3 6240 Comedo Invas. 42 _
5690 Comedo Invas. 59 _
Occult Tl 15 MRM NED 31
Occult Tl 31 MRM NED 9
NOS = Not otherwise specified; * Clinical stage is based upon the palpable or mammographic local excision; MRM = Modified radical mastectomy; NED = No evidence of disease.
cer; the failure rate has been reported as greater for palpable than radiographically detected in situ cancers (7). In our study, the pathologic size of mammographically detected lesions was 0.9 cm, as compared to 1.95 cm for symptomatic patients. Despite this apparent difference in tumor burden, there was no difference in the rate of local failure between these subsets of patients. All patients were treated with local excision of all gross tumor. Surgical margins of only 2 l/77 (30%) of specimens were assessed pathologically and only one local failure occurred in this group. Five local failures occurred in patients whose surgical margins were not evaluated pathologically. It is possible that some patients whose margins were not evaluated had a substantial number of clonogenic malignant cells remaining in the breast, which could not
80 6
Comedo(n=27)
F 5 0
60 PcO.03
a
failure
5 0
Comedo Invas. 52 + Occult Tl 23 WLE + RT NED 25
6 6040 Comedo Invas. 40 _ Occult T2 53 MRM NED 4
size of the lesion; WLE = Wide
be controlled with conventional doses of irradiation. McCormick et al. ( 12) reported that 30% of their patients with local recurrence had close or involved margins and only 4% of locally controlled patients had positive/close margins. Careful attention to surgical margins through routinely blotting the surface of the specimen with India ink prior to sectioning and orienting the specimen, is recommended in breast conservation therapy for intraductal breast cancer (6, 7). Within the past decade, there has been a trend towards the elimination of axillary dissections in patients with intraductal breast cancer because of the extremely low incidence of metastasis. Fisher et al. (5,6) found no positive nodes in 78 patients registered in the National Surgical Adjuvant Breast Project (NSABP) protocol B-06. In NSABP Protocol B 17, an axillary dissection was initially required, but this stipulation was dropped in the midst of patient accrual because of preliminary results. Recently Silverstein et al. (2 1) reported one of 183 patients (0.5%) with a positive axillary dissection. We do not recommend axillary dissection unless the nodes are palpable, or the mammographic extent ofthe intraductal carcinoma is diffuse (greater than 4 cm), increasing the odds of a sampling error for microinvasive or frankly invasive cancer (10, 11). Irradiation of the regional lymph nodes, as reported by Zafrani (25) in some patients, is also not necessary. Seventy of 77 breasts (9 1%) in this study were irradiated. Table 7. Intraductal Cosmesis
carcinoma of the breast: scoring criteria
20
0-
1
1
I
I
I
I
1
2
3
4
TIME
(years)
Fig. 2. Intramammary control by histology-Comedocarcinoma vs. other histologic subtypes of ductal carcinoma in situ.
1 5
Excellent: Minimal or no difference in the size, shape, or texture; Slight thickening or scar tissue permissable Good: Mild asymmetry; Slight reddening or darkening of the breast; Some thickening or scar tissue Fair: Obvious difference in the size, shape, and texture; Moderate thickening or scar tissue; Obvious color changes Poor: Marked change in the appearance, involving more than a of the breast tissue; Obvious skin changes; Severe scarring and thickening
Breast conservation for DCIS 0 R. R. KUSKE et
The importance of radiotherapy to the intact breast following wide local excision is a source of considerable debate and investigation in the recent literature. This issue is the focus of NSABP Protocol B 17, which closed in December 1990; results will not be available until the data matures. In our analysis, irradiated patients had fewer local failures than those in the excision alone group, but the small number (7) in the excision-alone group makes us reluctant to draw conclusions despite the statistical significance. Patients refusing radiation did not have worse prognostic indicators. Pathologic size, percentage of comedocarcinoma histology, clinical features, and surgical factors were comparable between the two groups. With excision-alone, multicentricity is a major concern. According to Lagios (lo), 54% of intraductal carcinomas larger than 2.5 cm were multicentric. In our study, 6 of 7 breasts (86%) treated with excision alone had a tumor size less than or equal to 2.5 cm, which yields an increase of multicentricity of only 14%. The fact that all of the comedocarcinomas in the unirradiated group versus 3/25 ( 12%) of the irradiated group experienced local failure suggests that this histologic subtype may not be suitable for local excision alone. Further, all three of our local recurrences following irradiation were comedocarcinoma, lending credence to the hypothesis that this histologic subtype may be more biologically aggressive. Silverstein et al. (2 1) noted an 11% incidence of local recurrence in 53 patients treated with local excision and irradiation of comedocarcinoma compared with 2% (l/5 1) of other types of DCIS treated with breast conservation. In contrast, Bornstein et al. (1) observed a 22% incidence of local recurrence (6/27) in patients with comedocarcinoma vs. 20% (2/ 10) in those with other subtypes, all treated by excision and irradiation. Lagios et al. (11) treated patients selected according to strict criteria with wide excision alone between 1972 and 1987. The recurrence rate was 19% (7/36) in patients with comedocarcinema or cribriform with necrosis in contrast to 0 of 33 patients with a micropapillary histology and l/ 10 ( 10%) with cribriform with anaplasia (Q = 0.028). It should be emphasized that histologic patterns are frequently diverse, and that our study and others report the predominant patsubtype. Fisher et al. (5) found pure or predominant terns in only 6-2 1%. Zafrani et al. (25) found more than one subtype in 48%. One possible explanation of these findings is that comedocarcinoma has a higher proliferative index compared to other histologic subtypes, leading to earlier recurrence and accounting for a higher failure rate early in the study. It is possible that the local failure rate of other histologic subtypes will ‘catch up’ when current studies achieve 10 to 15 year follow-up. Meyer (13) noted that comedocarcinema had a significantly higher thymidine labeling index and S-phase fraction, compared to other histologic subtypes. Van der Vijver et al. (24) reported that solid and comedo subtypes of DCIS over express the neu-protein as compared to small-cell, papillary, or cribriform types.
al.
395
Fentiman et al. (4) and Patchefsky et al. (16) noted relatively greater numbers of mitoses and increased cellular pleomorphism in comedocarcinoma, and more diffuse extension of this DCIS subtype in the excision specimen. However, Patchefsky et al. (16) found no multicentricity within the comedo subtype, compared to 80% for micropapillary, 36% for papillary, and 27% for solid/cribiform. Further, they concluded that small nonpalpable cribriform histologies should be treated by wide local excision alone, without breast irradiation, and recommended irradiation for micropapillary and papillary subtypes because of a greater incidence of multicentricity. Fentiman et al. (4) found 23% of comedo specimens multicentric and approximately the same percentage of multicentricity in all other subtypes. All six intramammary failures in our series were successfully salvaged with further surgery (Table 6). Of concern, however, is that four of the six local recurrences (67%) were invasive carcinoma. This finding of approximately 50% invasive carcinomas in intramammary recurrences is similar to other series (21). Patients failing with invasive carcinoma are at risk for distant failure with continued follow-up, but the rate of distant failure in the studies published to date show no significant difference between patients treated with mastectomy and conservation therapy (2, 8, 9, 14-16). Close surveillance after treatment is critical, since early detection of the 7% to 10% who may fail by 5 years will allow optimal salvage surgery for cure. We see our patients as a team every 3 months for the first year, every 4 months for the second year, and every 6 months thereafter. Ipsilateral mammograms are performed at 6-month intervals from the completion of irradiation for the first 2 years, then yearly. Patients treated with breast conservation therapy for intraductal breast cancer as an alternative to mastectomy will still have breast tissue at risk of developing breast cancer. This risk may be higher with comedocarcinoma especially if the breast is not irradiated. However, as long as salvage surgery proves successful and the overall survival rates are comparable to those after initial mastectomy, many patients will continue to choose breast conservation therapy as local treatment for DCIS as well as invasive ductal cancer. In our study, quality of life in patients undergoing conservation surgery and irradiation was excellent, with an 85% excellent/good cosmesis rate, and minimal complications. Every patient stated retrospectively that she would choose conservation therapy again (the four patients treated with modified radical mastectomy for intramammary recurrences were not questioned after surgery). Further studies with larger numbers of patients and long term follow-up are required to address the issues raised by these data. Criteria for inclusion in such studies should be carefully defined and perhaps broadened, since, as noted by Fentiman et al. (4) in an EORTC trial, only 77 of 2 16 (36%) eligible patients were actually entered in this study.
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1. .I. Radiation Oncology 0 Biology 0 Physics
Questions remain. Will a significantly higher percentage of irradiated patients retain their breast at 10 years compared with patients treated with excision alone, because of a decrease in the rate of local recurrence? Does comedocarcinoma histology contraindicate local excision alone,
Volume 26, Number 3, 1993
or even local excision and irradiation? Will pathologic assessment of surgical margins aid in selecting patients? And will the overall survival rate at 10, 1.5, or 20 years be comparable to that of patients treated with mastectomy?
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