Breast Cancer Vol. 8 No. 4 October 2001

Special Lecture II

Trealment Selection in Ductal Carcinoma in situ

Monica Morrow

Breast Cancer 8:275-282, 2001.

Key words: Intraductal carcinoma, Surgery, Lumpectomy

The appropriate local therapy for ductal carcino- ma in situ (DCIS) is controversial, and total mastec- tomy, excision and irradiation, and excision alone have all been advocated as management strategies. This wide variety of treatment options results from uncertainty about the natural history of DCIS, with those who regard the disease as an obligate precur- sor of malignancy advocating traditional cancer treatments and those who believe that not all DCIS will progress to invasive carcinoma favoring a poli- cy of excision and observation in selected cases. To some, the dramatic increase in the detection of DCIS which corresponds to the increased use of screening mammography suggests that some of the DCIS seen today is biologically indolenf ). How- ever, a comparison of risk factors for DCIS and invasive cancer in a cohort of 37,105 women in which 1,240 incident breast cancers occurred demonstrat- ed no differences in risk factors, or the magnitude of risk conveyed by these factors, between women with invasive carcinoma and DCIS 2). This suggests that both entities are part of the same biologic process.

Mastectomy Mastectomy is a curative treatment for about

98% of patients with DCIS, whether gross or non- palpable, and a therapy for which all patients are eli- gible ~1~ As illustrated in Table 1, most of the data on the efficacy of mastectomy comes from patients

Lynn Sage Breast Program and Department of Surgery, Northwestern Uni- versily, USA. Reprint requests to Monica Morrow, Department of Surgery, Northwestern University, 675 N. St. Clair Street, Gaiter 13-174, Chicago, IL 60611, USA. E mail: mmorrow@nmh.org

Abbreviations: DCIS, Ductal carcinoma in situ; NSABP, National Surgical Adjuvant Breast and Bowel Project; EORTC, European Organization for Research and Treatment of Cancer

with clinically evident DCIS. In spite of the fact that clinically evident DCIS might be more biologically aggressive than its mammographic counterpart, recurrences after mastectomy are rare. Recurrent carcinoma after a mastectomy for DCIS may be due to undiagnosed invasive carcinoma present at the time of mastectomy or incomplete removal of the breast tissue with the subsequent development of a new carcinoma. The failure of recurrence rates after mastectomy to increase with longer follow-up intervals suggests that the majority of recurrences are due to undiagnosed invasive carcinoma rather than the malignant transformation of residual breast tissue.

Until recently, mastectomy was the most com- mon treatment for DCIS in the United States. Analysis of DCIS treatment data collected by the National Cancer Institute's Surveillance, Epidemiol- ogy and End Results (SEER) Program between 1983 and 1992 revealed a significant decline in the proportion of DCIS cases treated by mastectomy in the US (from 71% to 43.8%) and an increase in those treated by lumpectomy (from 25.6% to 53.3%) 1)

Breast-Conserving Therapy A variety of factors have stimulated interest in

the treatment of DCIS with less than total mastecto- my. These include the large increase in the number of clinically occult cases of DCIS being identified by screening mammography, uncertainty regarding the natural history of mammographically detected DCIS, and the acceptance of breast-conserving therapy (BCT) for the treatment of invasive carci- noma.

Breast Conservation with Excision and Irra- diation

The acceptance of breast-conserving therapy as a treatment for invasive carcinoma has led to the

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Table 1. Results of Treatment of DCIS with Simple Mastectomy

Treatment of DCIS

Author Years Follow-up No. Patients % Nonpalpable No. Recurrences

Sunshine et al. 3~ 1960-72 10 years 74 0 4 Von Rueden and Wilson/~ 1960-81 ? 45 9 0 Ashikari et al. ~ 1965-75 11 years 92 0 0 Schuh et a l? I 1965-84 5.5 years 51 33 1 Kinne et al. 71 1970-76 11.5 years 101 59 1 Arnesson et al. 81 1978-84 77 months 28 1 O0 0 Ward et al. 91 1979-83 10 years 123 20 1 Silverstein et al.~~ 1979-96 80 months 228 72 2

Table 2. Results of Treatment of DCIS by Excision and Irradiation

Author No. Patients Follow-up (mos) % Recurrence % Invasive

McCormick et al. H~ 54 36* Silverstein et al. 121 185 90 +

Silverstein et al. 13) 2 1 3 81 *

Ray et al. ~41 56 67*

Hiramatsu et al. ~53 76 74 + Fisher (B06) et al. ~1 27 83* Stotter et a l Y ~ 42 92 + Solin et al. ~81 268 130 +

Fisher et al. (B17) '9) 411 90* EORTC 2~ 502 51 +

18 30 13/22 53

(5/1 O-year actuarial) 17 51 9 20 9 57 7 5O 9 100

19 53 (15-year actuarial)

11 36 11 45

*mean +median

use of excision and irradiation to treat DCIS. No randomized trial has directly compared the treat- ment of DCIS by mastectomy to treatment by exci- sion and irradiation, and such a trial is unlikely to be done. The assumption that since these two treat- ments have been repeatedly shown to result in equal survival for patients with invasive carcinoma the same will be true for patients with DCIS is flawed, due to the fundamental difference between invasive carcinoma and DCIS. In patients with inva- sive carcinoma, the risk of metastatic disease is pre- sent at the time of diagnosis and, in most cases, is not altered by local recurrence in the breast. In DCIS, the risk of metastases at the time of diagno- sis is negligible, and an invasive local recurrence carries with it the risk of increased breast cancer mortality. The appropriateness of excision and irra- diation as a treatment for DCIS should be deter- mined by the incidence of invasive recurrence in the breast and the results of salvage therapy.

A number of authors have reported their experi-

ences with excision and irradiation for the treat- ment of DCIS, and these reports are summarized in Table 2 I1-~~ Solin et al . 1~) reported the results of 268 women with 270 breasts treated with excision and irradiation and followed for a median of 10.3 years. Gross excision of the tumor was carried out in all cases, but margin status was unknown in 120 cases and only 15% of patients underwent reexci- sion. The median whole-breast dose of radiation was 50 Gy, and 65% of patients received a boost to the primary tumor site. Forty-five local failures were observed, and the 15-year actuarial rate of local failure was 19%. The median time to local fail- ure was 5.2 years, but 14% of the recurrences were seen after 10 years of follow-up. Half of the local recurrences were invasive carcinoma, and the 15- year cause-specific survival was 96%. However, a separate analysis of 42 patients who recurred demonstrated a 5-year actuarial cause-specific sur- vival rate of 85% for this subgroup of patients TM. This study is noteworthy for the large number of patients

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Table 3. Results of Treatment of DCIS by Excision Alone

Author No. Patients Follow-up (mos) % Recurrence % Invasion

Carpenter et al. 231 28 38*

Schwartz et al. 2~1 194 53 +

Baird et al. ~1 30 43* Silverstein et alJ ~ 130 45 +

Silverstein et al. '3~ 256 81 * Arnesson et al. 26~ 169 80 +

Fisher et al. (B06) '6~ 21 83* Gallagher et al. 271 13 1 O0 +

Millis & Thynne 281 9 120* Lagios et al. 3~ 79 130 +

Fisher etal. (B17) ~9) 403 90* EORTC 2~ 500 51 +

18 20 14/25 18

(5/10-year actuarial) 13 25

21/35 33 (5/10-year actuarial)

15 42 16/22 36

(5/1 O-year actuarial) 43 55 38 60 22 100 18 56

(15-year actuarial) 26 51 17 48

*mean +median

and the long duration of follow-up. Although many of the surgical excisions would not be considered ade- quate by today's standards, the 15-year cause-spe- cific mortality for the entire group was low, sup- porting the idea that excision and irradiation is a safe therapy.

Solin and coauthors performed a separate analy- sis of 110 patients with clinically occult, mammo- graphically detected tumors ~2~. The 10-year actuarial rate of local recurrence in this series was 14%, and the median interval to recurrence was 5 years. These figures do not differ significantly from those seen in their larger series, which included patients with both clinically evident and mammographically detected DCIS.

Breas t Conservation with Excision Alone A number of investigators have examined the use

of excision alone as a treatment for DCIS ~' 1,~. 19. ~2~) The majority of these studies suggest that patients with large, high-grade DCIS lesions are poor candi- dates for treatment with excision alone. In most studies of treatment by excision alone, patients have been highly selected, usually on the basis of small lesion size and low histologic grade or absence of comedonecrosis. Schwartz et al. '29~ identified only 70 patients between 1978 and 1990 who were eligi- ble for excision alone, while Silverstein e t al . 1~

found that approximately one third of 333 patients in his series underwent excision alone. Solin et al. '~

retrospectively applied criteria for treatment by excision alone to a group of 110 patients with mam- mographically detected DCIS treated by excision and irradiation and found only 21 suitable patients.

Recurrence rates after excision alone range from 13% to 43%, and are highly dependent on the patient selection criteria employed, method used to calculate the recurrence rate, and length of follow- up10,1:~, 16,19, 2:~29~ (Table 3). In general, higher rates of local failure are observed in studies that include clinically evident DCIS and those with longer fob low-up periods 16'~7).

More recently, Silverstein et al. 13) suggested that all DCIS was appropriate for treatment with exci- sion alone, provided that a margin of normal breast tissue of 1 cm or more was obtained in all direc- tions. This was a retrospective study of 469 patients who had been treated with breast-conserving surgery with or without postoperative radiation therapy. At eight years of follow-up, no difference in the incidence of local recurrence between patients treated by excision alone and those treated by exci- sion and radiotherapy was seen if margin width was greater than 1 cm. However, lesions treated with excision alone were significantly smaller than those treated with radiotherapy. Perhaps more important- ly, treatment with excision alone was more frequent in the later years of the study, raising the possibility that improvements in mammography and patholog- ic evaluation may be responsible for some of the

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outcomes. This is well illustrated in the study of Hiramatsu and coworkerd 5), in which local failure rates of patients treated with excision and radio- therapy from 1976 to 1985 and from 1986 to 1990 were compared. The incidence of local failure decreased from 12% to 2% at 6.5 years, although the dose of radiotherapy did not change. This strongly suggests that findings from retrospective studies in which patients are accrued over long periods of time cannot be regarded as definitive, but should serve as the basis of prospective studies.

Breast recurrences after the treatment of DCIS by excision alone are evenly divided between inva- sive carcinoma and recurrent DCIS in the majority of reports (Table 3). A notable exception to this is the report of Schwartz et al. 24' :~o), in which only 24% of breast recurrences were invasive carcinoma. The likelihood of invasive recurrence is the critical determinant of outcome in DCIS, since recurrent intraductal carcinoma carries no risk of breast can- cer mortality. Whether the high incidence of nonin- vasive recurrence in the Schwartz study was due to aggressive mammographic surveillance or the suc- cessful identification of a subset of patients with DCIS of low malignant potential is uncertain.

Randomized Trials of Breast Conservation Data from three prospective, randomized trials

are available to address the question of the benefit of radiation therapy in the treatment of DCIS. The National Surgical Adjuvant Breast and Bowel Pro- ject (NSABP) protocol B-06 was designed to evalu- ate the local therapy of invasive carcinoma '6). Seven- W-eight patients with DCIS alone were identified on review of pathologic material. At a mean follow-up of 83 months, no local failures were observed in the 28 patients treated by mastectomy, compared to a 7% (2 of 27) local failure rate in the patients treated with irradiation, and a 43% (9 of 21) failure rate in patients treated with lumpectomy alone.

The NSABP also reported the results of B-17, a trial specifically designed to evaluate the role of radiation therapy in DCIS 19' 3,. In this study, 818 patients were randomized to excision alone or exci- sion plus 5,000 cGy of irradiation to the breast. His- tologically negative margins, defined as tumor-filled ducts not touching inked surfaces, were required, and only 9% of the irradiated patients received a boost dose to the tumor bed. Eighty percent of the patients in the study had mammographical ly detected tumors. At a mean follow-up of 90 months, there was a 59% reduction in the annual incidence

of ipsilateral breast cancer recurrence in the irradi- ated group. Although the incidence of both invasive and intraductal breast recurrence was reduced by radiation, the main benefit of radiation was in reducing invasive recurrences; while the rate of noninvasive cancer was reduced by 47%, the rate of invasive cancer was decreased by 71%. At 8 years of follow-up, the recurrence rate of DCIS was reduced from 13.4% to 8.2% (p = 0.007) with the addition of radiation therapy, and the incidence of invasive breast recurrence from 13.4% to 3.9% @<0.0001). However, there was no significant difference in overall survival between the groups at 8 years, with a 94% survival in the lumpectomy group and a 95% survival in the lumpectomy plus radiation group. A subsequent pathologic analysis of 623 of the patients enrolled in the study assessed the relation- ship between pathologic variables and breast recur- rence at 8 years of follow-up, in an effort to identify subgroups of women who did not benefit from irra- diation and, conversely, of women who were at increased risk for breast cancer recurrence:% Over- all, the frequency of local failure was reduced from 31% to 13% (p = 0.0001) by radiation therapy. The only pathologic feature shown to be an indepen- dent risk factor for breast cancer recurrence was moderate to marked comedonecrosis. A subgroup of patients who did not benefit from radiotherapy could not be identified in this study. For the most favorable subgroup, those with absent or slight comedonecros i s and negative margins , the absolute benefit of radiotherapy was a 7% reduction in recurrence at 8 years. Based on these findings, the authors concluded that the use of irradiation is appropriate for all patients with intraductal carcino- ma, although the magnitude of benefit will vary with the absolute risk of recurrence.

The results of the NSABP study have been criti- cized as being inadequate to address the question of whether some patients with DCIS do not require radiation therapy 33~ due to failure to evaluate speci- mens with the detailed pathologic and mammo- graphic techniques in use today to determine the size of a lesion and the completeness of resection. While this is true, this randomized study clearly demonstrates that when DCIS is evaluated using standard mammographic and pathologic tech- niques available in any hospital, the use of irradia- tion will reduce the risk of a breast recurrence.

The third and most recent prospective, random- ized study to address the benefit of radiotherapy was the European Organization for Research and

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Treatment of Cancer (EORTC) trial 108532~ In this study, 1,010 women with DCIS of 5 cm or less in size were treated with excision to negative margins and randomized to no further treatment or to whole-breast radiotherapy (50 Gy over 5 weeks). The 4-year relapse-free survival rate was 84% in the group treated with excision alone and 91% in the group treated with excision plus radiotherapy (p = 0.005). Risk reduction for recurrent DCIS was 35%, and for recurrent invasive tumor was 40%. The results of this trial confirm the findings of NSABP B-17, that there is a benefit for radiotherapy in DCIS, but fail to support a differential effect on invasive recurrence.

Treatment Selection Although all patients with DCIS are candidates

for mastectomy, many can also be treated with breast preservation with or without irradiation. The evaluation of a patient's suitability for breast preser- vation begins with an assessment of the extent of the DCIS lesion. Magnification mammography is essential for this evaluation. Holland et al. ~' 35) have noted that conventional two-view mammography (craniocaudal and mediolateral oblique views only) underestimates the extent of well-differentiated DCIS by 2 cm in 47% of cases. The use of magnifica- tion views reduces this discrepancy to only about 14% of cases. An accurate determination of lesion size allows preoperative selection of those patients who are appropriate candidates for breast preserva- tion and minimizes the number of surgical proce- dures that are needed to achieve an adequate nega- tive margin. Morrow et al. 3~), reported the results of magnification mammography in 263 patients, includ- ing 51 with DCIS, who were clinical candidates for breast conservation. Breast preservation was suc- cessfully carried out in 97% of patients found to have localized tumors by magnification mammog- raphy compared to only 38% of patients with exten- sive multifocal or multicentric disease identified by mammography. Kearney and Morrow 37) reported 173 patients evaluated with magnification mam- mography, in whom a diagnostic excision to negative margins was attempted. Negative margins were obtained in 161 patients (93%) with a single surgical procedure. These data indicate that the extent of DCIS can be identified preoperatively in the majori- ty of patients, avoiding attempts at breast preserva- tion in those with extensive disease.

Needle localization should be used to guide the excision of all nonpalpable lesions. Placement of

the biopsy guide within 1 cm of the target will allow removal of the lesion with a limited amount of normal breast tissue, and is an achievable goal 3s). Bracket- ing wires may be useful in patients with extensive calcifications who are candidates for breast-con- serving surgery, but we do not find them neces- sary for routine cases. Placement of the surgical incision over the area of pathology, rather than at the entry point of the wire, improves exposure and often allows the use of a smaller incision. Electro- cantery should be avoided until after the specimen is removed, since cautery may distort or destroy small lesions, making an accurate pathologic diag- nosis difficult or impossible. Specimen mammogra- phy is essential to confirm the excision of calcifica- tions. In cases where calcifications are extensive or approach the edge of the surgical specimen, pos- texcision mammograms are useful to confirm the removal of all suspicious calcifications. Gluck et

a l Y ), did postexcision mammograms with spot compression views on 43 women who required reexcision for positive or unknown margins after a diagnosis of breast carcinoma. Twenty-eight patients had DCIS, and the positive predictive value for residual calcifications as an indicator of residual tumor was 0.67, which increased to 0.9 when more than five calcifications were present. Waddell and associates 3~) reported similar findings in a retro- spective review of 67 patients treated for DCIS between 1995 and 1998 who underwent postexci- sion mammography. Residual microcalcifications were identified in 16 patients (24%). Twelve patients underwent wide reexcision and two patients under- went mastectomy. Residual DCIS was identified in 9 of 14 patients (64%). These studies confirm that postexcision mammography can be a valuable adjunct to specimen radiography and pathologic analysis to ensure that adequate excision of DCIS has been achieved. The demonstration that DCIS, par- ticularly low- to intermediate-grade lesions, grows in a discontinuous fashion 4~ indicates that a signifi- cant amount of residual tumor may be present at the biopsy site even when the margin is negative. Thus, margin status and postexcision mammogra- phy are complementary means of assessing the adequacy of resection.

Although core biopsy is the diagnostic proce- dure of choice for indeterminate calcifications (BIRADS 4), for highly suspicious calcifications (BIRADS 5) suitable for treatment with a breast- conserving approach, we have prospectively demon- strated that a diagnosis with core biopsy does not

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offer any advantages over needle localization and excision as far as achieving negative margins with a single excision 41~.

Contraindications to breast preservation with excision and irradiation are similar to those defined for invasive carcinoma 4e). These include a history of therapeutic irradiation to the breast, evidence of multicentric tumor, and diffuse indeterminate or malignant-appearing microcalcifications that would preclude follow-up. A large tumor-to-breast ratio is a relative contraindication. Although high-grade or comedo DCIS has a higher rate of short-term recurrence than low-grade DCIS, the presence of high-grade histology alone is not a contraindication to breast conservation treatment since the majority of these patients will not experience local failure. Contraindications to breast preservation with exci- sion alone are less well defined. However, recur- rence rates for gross DCIS, high-grade or comedo lesions, and large areas of DCIS (> 20 ram) treated by excision alone are high, and these findings are considered contraindications in most centers. The inability to salvage a patient treated by excision alone with further excision and irradiation (for example, due to small breast size) is a relative con- traindication to t rea tment by excision alone. Although the ability to treat local recurrence with further breast preservation with reexcision and irradiation is one of the advantages of initial treat- ment with excision alone, only 44% of patients in NSABP B-17 underwent such therapy after recur- rence al).

An increasing number of studies suggest that patient age may influence outcome in DCIS. Solin et al. '2'~ observed a 25% rate of local failure in patients treated with excision and irradiation aged 50 or younger as compared to 2% in patients older than 50, in spite of the fact that nuclear grade, tumor size, and margin status did not differ between groups. The median time to local failure was also shorter in the younger patients (4.9 years vs. 8.7 years). Vicini et al . 4a) reviewed 146 patients diag- nosed with DCIS and treated with breast conserva- tion followed by radiation therapy from 1980 to 1993. The rate of local failure at 10 years was 26.1% in patients younger than 45 years of age versus 8.6% in older women. The difference in invasive recur- rence was especially noteworthy, with younger patients having a 19.9% incidence of invasive recur- rence at 10 years, while women 45 years of age and older had only a 3.2% rate of invasive recurrence. In multivariate analysis of factors associated with inva-

sive failure, only nuclear grade and patient age were independent predictors. Van Zee et al. 44~, also observed higher rates of local failure after treat- ment with excision and irradiation or excision alone in women under age 40 than in their older counterparts. However, the addition of breast irra- diation to excision did reduce the rate of local fail- ure in all age groups. The results of these retro- spective studies were confirmed in the NSABP B- 24 trial. Local recurrence rates after treatment with excision and radiotherapy were 3.3% in women under age 49 years compared to 1.3% in women age 50 years and older 4~). A possible explanation of these results may be the presence of higher circulating lev- els of estrogen in the younger patients, since estro- gen has known promotional effects on breast can- cer cell lines.

Other studies have suggested that a family his- tory of breast cancer may impact on the risk of local failure after excision and irradiation. McCormick et alJ 1~ reported that 40% of patients failing locally had a family history of a first-degree relative with breast cancer versus 11.4% of patients in whom local control was maintained. Similarly, Hiramatsu et al. ~ observed a 37% failure rate in patients with a family history of breast cancer com- pared to 9% in those without a family history. Szelei- Stevens eta/ . 46) evaluated the combined influence of family history of breast cancer and young age on outcome by treatment method. One hundred twen- ty-eight patients with DCIS were treated with mas- tectomy, lumpectomy alone, or lumpectomy and radiation, with a median follow-up of 8.7 years. Patients with a positive family history had a 10.3% local recurrence rate (LRR) versus a 2.3% LRR in patients with a negative family history. Of women 50 years of age and less, the LRR was 9.1% com- pared to 2.4% for women over 50 years. Women with a positive family history younger than 50 years had a LRR of 20%. Importantly, all women who recurred had undergone lumpectomy alone.

After determining a patient's suitability for breast preservation, treatment options should be discussed in detail. The risk of recurrent DCIS and invasive breast cancer, the treatment implications of a recurrence, and the risk of breast cancer death should all be considered. The risk of breast cancer death 10 years after a mastectomy is 1-2%. It is like- ly that the major force of breast cancer mortality will be evident in the first 10 years after treatment, given that death is presumably due to occult microinvasive disease present at the time of diagno-

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sis. The risk of death after excision and radiation at 10 years is about 3%, little different than that seen after mastectomy. However, since the time to local recurrence is often prolonged, it is likely that addi- tional breast cancer-associated mortality will occur after 10 years, and comparisons of breast cancer mortality rates 30 years after treatment may show greater differences than those discussed here. The importance to patients of these small differences will vary, and patient age will certainly influence treatment selection. On the other hand, improve- ments in patient selection in recent years are likely to result in fewer breast recurrences than reported in currently available studies with 10- and 15-year follow-up periods. The addition of tamoxifen to local therapy offers the opportunity for additional risk reduction 45). Today, a spectrum of treatments rang- ing from excision alone to excision plus radiothera- py, excision, radiotherapy, and tamoxifen, or mas- tectomy is available for women with DCIS. The chance of breast cancer death is small with each approach, and individual attitudes toward risk and benefit will play a major role in treatment selection.

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