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Locally recurrent breast cancer after conservation therapy
The American Journal of Surgery 189 (2005) 229 –235
Review
Locally recurrent breast cancer after conservation therapy Tara L. Huston, M.D., Rache M. Simmons, M.D.* Department of Surgery, The Weill Medical College of Cornell University, The New York-Presbyterian Hospital, 425 E. 61st St., 8th Floor, New York, NY 10021, USA Manuscript received January 30, 2004; revised manuscript July 16, 2004
Abstract Background: Today, the majority of small invasive and noninvasive breast cancers are treated with breast conservation therapy (BCT). The incidence of local-regional recurrence (LRR) after BCT for stage 0, I, and II patients ranges between 5% and 22%. Methods: A literature search for BCT, local recurrence, and regional recurrence was performed. Data from over 50 articles pertaining to the characteristics, risk factors, detection, management, and prognosis of these patients with LRR after BCT were collected and analyzed. Results: Positive margins, high-grade ductal carcinoma in situ (DCIS), young age, and the absence of radiation therapy after BCT increase the risk for LRR. Prognosis at LRR is impacted by invasive versus noninvasive histology, size and stage, method of detection, and involvement of skin and/or axillary lymph nodes. The standard treatment is salvage mastectomy. Conclusions: The prognosis for LRR after BCT is favorable compared with patients with postmastectomy chest wall recurrence. © 2005 Excerpta Medica Inc. All rights reserved. Keywords: Breast cancer; Breast conservation therapy; Local recurrence; Regional recurrence
The majority of small invasive and noninvasive breast cancers are treated today by breast conservation therapy (BCT), which includes wide local excision and radiation treatment to the breast. Multiple prospective randomized clinical trials, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04, B-06, and B-17 trials, and the Milan Institute Quandrantectomy versus Radical Mastectomy trial, showed no statistically significant difference in patient survival with mastectomy and breast conservation for small invasive and noninvasive carcinomas [1–10]. The incidence of local-regional recurrence (LRR) after BCT for stage 0, I, and II patients ranges between 5% and 22% [3,7,9,11]. The characteristics, risk factors, detection, management, and prognosis of patients with LRR after BCT are discussed in this collective review.
Characteristics of Local-Regional Recurrences Although all LRR after BCT generally are grouped together, it is important to appreciate that there are several * Corresponding author. Tel.: ⫹1-212-821-0853; fax: ⫹1-212-8210832. E-mail address: [email protected]
different types of recurrences that may reflect both cause and patient prognosis. The types of LRR are categorized by location of the breast recurrence in comparison with the primary treated breast carcinoma. The most common type of LRR, present in 57% to 88% of patients [11–15], appears at the site of the primary breast cancer and probably represents incomplete resection of the initial carcinoma. The second type, which consists of approximately 22% to 28% of LRRs, is within the same quadrant but not directly at the site of the initial carcinoma. These are hypothesized to represent evolution of multifocal ductal carcinoma in situ (DCIS) since the time of the original surgery. The third type of recurrence is found within a different quadrant from the initial breast cancer. These remote LRRs are found in 10% to 12% of patients and likely represent a new primary breast cancer [12]. The fourth type of LRR is the rare radiation-induced carcinoma within the radiated treatment field of the initial primary carcinoma [12]. The fifth category of LRR is a diffuse or inflammatory recurrence, detected in less than 5% of patients (see Fig. 1) [13]. The majority of patients who sustain LRR do so within 2 years [16,17]. The greater the time interval between the initial diagnosis and the LRR, the more likely it is that the recurrence will be located in a remote area of the breast
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Fig. 1. Sites/types of LRR after BCT [12]. Adapted with permission.
[11,12,18]. Those patients with LRRs in the vicinity of the original tumor recurred an average of 33 months after BCT, versus those with a LRR in a distant location, who recurred an average of 75 months after BCT [15]. These data suggest a treatment failure with the early recurrences at the original site and the development of a new primary cancer, with the later recurrences in remote areas. LRRs after BCT may be either invasive or in situ carcinoma. For women who initially were treated for invasive carcinoma, about 80% recur with invasive carcinoma, whereas the remainder have a DCIS recurrence [19]. In patients initially treated for DCIS, slightly more than half will recur with invasive breast carcinoma, while slightly less than half will have DCIS [20,21]. A small percentage of both invasive carcinoma and DCIS patients will be found to recur with either invasive lobular carcinoma or angiosarcoma [20].
Factors Associated With Increased Risk for Local Recurrence Margin status One of the most important predictors of increased risk for LRR is pathologic margin status after BCT. Margin status typically is described as negative, close, or positive. Controversy exists in the literature regarding the meaning of a close surgical margin, with definitions ranging from less than 1 cm to less than 1 mm. According to the NSABP, a margin is positive only if tumor cells are present at the inked surface. A close margin requires cancer cells to be within 1 mm of the inked margin and a negative margin implies that there is at least a 1-mm rim of normal parenchyma between the tumor and the margin. Positive margins are focal if observed in 3 or fewer power fields or diffuse if found in more than 3 power fields [22–25]. The majority of data show that close or positive margins result in an increased rate of LRR. In one series of 303 invasive breast cancers treated with BCT, patients with negative surgical margins had a 98% probability of local
control at 10 years versus a probability of only 82% in those patients with close or positive margins (P ⫽ .007). Another study showed that patients with negative final margins had 100% local control versus 78% for those without negative margins (P ⫽ .0001) [23]. These data emphasize the importance of obtaining pathologic tumor-free margins at the time of resection or re-excision to optimize local control. An extensive intraductal component (EIC) within an invasive breast cancer generally indicates a larger subclinical tumor burden and an increased likelihood of microscopically positive margins. When the margins are revised to a negative status, recurrence rates then decrease and become equivalent to women without an extensive EIC. In the presence of an EIC, negative margins strongly are recommended. Because revision of margins is equivalent to initial negative margins, it is important to recognize that these patients are not automatic mastectomy candidates [26]. Additionally, there are data to suggest BCT with a radiation boost to the surgical bed, in patients with a close or focally positive margin, generates equal or similar LRR rates as a negative margin [22,24,27]. Solin et al [22] compared nearly 700 women with invasive breast cancer and negative margins (⬎2 mm), positive margins, close margins (ⱕ2 mm), or unknown margins after BCT. All underwent a similar dose of definitive irradiation. There was no significant difference among the groups for 5-year overall survival, no evidence of disease survival, or relapse-free survival. Park et al [27] showed, with 8 years of follow-up evaluation, the LRR for all patients with positive margins was 18% compared with 7% for those with negative margins. However, the patients with a close (defined here as ⬍1 mm) margin had an equal rate of LRR to those with negative surgical margins. When the positive margins were analyzed further, those with a focally positive margin had an LRR of 14%, in contrast to the 27% LRR rate in those with extensively positive margins [27]. Thus, the actual amount of residual tumor in the excision bed is a significant predictor of increased recurrence. Histology of the primary tumor Pathologic characteristics of the tumor also affect the incidence of local recurrence. For more than 20 years, an EIC has been considered a risk factor for increased recurrence. Vicini et al [28] analyzed over 500 women with stage I or II breast cancer to determine the optimal extent of resection and found that an EIC was associated with a higher recurrence rate. For patients with EIC-positive (EIC⫹) tumors, the larger resections were associated with lower risks for recurrence when compared with the smallervolume resections. However, for women with EIC-negative (EIC⫺) tumors, the risk for recurrence was not influenced by the resection volume. The conclusion was that a generous resection volume is more important for EIC⫹ than for EIC⫺ breast cancers. There are 4 main types of DCIS: papillary, cribiform,
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solid, and comedo. By far, cribiform has been shown to carry the greatest risk for increased recurrence. Microinvasion with DCIS most commonly occurs when the subtype is comedo, especially when the lesion is dense and high grade. Tumor necrosis also is associated with an increased risk for recurrence [29]. In one study looking only at women who initially had DCIS, the pathologic characteristics in 83% of the local recurrences were unfavorable, having comedo subtype DCIS, as well as high nuclear grade for the intraductal and invasive components [30]. Silverstein et al [31,32] showed that nuclear grade and the presence of necrosis identifies a high-risk subgroup of DCIS for LRR. Patient age Whether young age is associated with a higher risk for LRR after breast conservation is controversial, however, several studies do show that younger patients have an increased incidence of LRR [33–38]. One retrospective analysis of 290 women with invasive breast cancer, treated with BCT, were subdivided by age at initial diagnosis. Women in the younger group, less than 35 years of age at initial diagnosis, were found to have higher rates of local recurrence and decreased rates of survival than those in the older age group, who were over age 35 at diagnosis (P ⬍.05). With multivariate analysis, age persisted as a statistically significant risk factor for LRR [39]. Similar results were shown by the Danish Breast Cancer Cooperative Group and the European Organization for Research and Treatment of Cancer, in which patients 35 years of age or younger had a 9.24 times higher risk for developing LRR after BCT than patients older than 60 years of age [40].
Fig. 2. Methods of detection of LRR [20].
BCT was decreased from 26.8% without radiation therapy to 12.1% with radiation therapy (P ⬍.000005) [8]. Likewise, the European Organization for Research and Treatment of Cancer 10853 protocol showed the 4-year LRR was 9% for patients treated with breast radiation after lumpectomy compared with 16% for those treated without radiation (P ⫽ .005) [44]. These results were confirmed by multiple other studies [41,45– 47]. Patients treated solely with local excision and not with adjuvant radiation have a shorter time to LRR [21,42,44]. There are studies showing excision alone may be appropriate in selected patients with DCIS. Patients who may be candidates for excision alone are those with small, lowgrade DCIS and generous, clear surgical margins [47,48].
Detection of Local Recurrence Radiation therapy Because of the potential multicentricity of breast cancer, the addition of radiation treatment to lumpectomy in patients with DCIS and invasive carcinoma generally is recommended. The NSABP B-06 trial evaluated the local recurrence of small invasive tumors with and without radiation after lumpectomy. The patients without radiation had a significantly higher rate of local recurrence [1,4,41]. These data have been substantiated by other series [42]. A retrospective subset analysis of the NSABP B-06 trial evaluated the treatment of DCIS by lumpectomy alone versus lumpectomy plus radiation. This study showed that women treated with lumpectomy alone had a 23% local recurrence rate, whereas only 7% of those who received adjuvant radiation had a local recurrence within a follow-up period of 53 months [43]. Because of the issues raised involving DCIS with the B-06 trial, the NSABP initiated a further trial, the B-17 trial, which randomized women with DCIS to those who would receive excision and radiation versus surgical excision only. The results of this trial showed that the 8-year rate of LRR for DCIS treated with
Patients should be screened for the early detection of LRR by breast imaging and clinical examination. LRRs are detected by mammography alone 42% to 75% of the time, by physical examination alone 10% to 33% of the time, by a combination of the physical examination and mammography in 12% to 25% of the time, and by other imaging techniques such as magnetic resonance imaging (MRI) 5% of the time (Fig. 2) [18,20,42]. Some data suggest that MRI may be a sensitive and specific test, in addition to mammography and physical examination, for the detection of LRR. Drew et al [49] showed a sensitivity of 100% and a specificity of 93% in the detection of LRR after breast conservation using breast MRI. This may be because scarring, distortion, and postsurgical changes in density are better characterized by MRI than by mammogram. MRI has become an increasingly useful clinical adjunct for the detection of recurrent cancer in a breast that already has undergone surgical, radiation, or drug therapy. MRI becomes most accurate for the identification of residual tumor 18 months after the cessation of radiation therapy because it takes about this period of time for areas of
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radiation fibrosis to diminish [50]. MRI is recommended for the detection of recurrence in the post-BCT breast, especially when conventional mammographic imaging is indeterminate or negative yet there is a high clinical suspicion for recurrence [51]. A biopsy examination of new findings on breast imaging or examination is recommended. It has been shown that microcalcifications in the site of the previous site of BCT represent a LRR in 58% of cases [52].
Management of Local Recurrence Unlike chest wall recurrences after mastectomy, LRR after BCT typically is not associated with distant metastases [11,34]. Because it would alter overall treatment decisions, it is reasonable to perform an extent of disease work-up with a computerized tomography scan and bone scan at the time of LRR. Between 5% and 12% of patients will be found to have inoperable disease at the time of diagnosis of LRR [11,53,54]. The treatment of choice for LRR historically has been salvage mastectomy. There are very limited data available on reconservation of the breast at LRR. Salvage mastectomy The generally recommended treatment for locally recurrent breast cancer after breast conservation is salvage mastectomy [12,16,20,53–55]. This procedure is relatively successful in controlling local disease, with the incidence of secondary LRR after salvage mastectomy ranging between 4% and 37% [53–55]. The median time to subsequent failure is 18 months (range, 2– 45 mo) [55]. The rate of secondary recurrence decreases with longer disease-free interval between BCT and first LRR [53–55]. Because of the inelasticity of previously irradiated breast skin, tissue expansion with breast reconstruction often results in a poor cosmetic result, thus an autologous tissue flap is the preferred method for breast reconstruction [12]. Reconservation surgery Some patients refuse salvage mastectomy and desire reconservation of the breast at LRR. For the majority of patients, BCT includes radiation treatment and thus needs to be avoided with reconservation therapy. New technologies are being explored that use localized radiation of the breast and may allow reconservation with additional localized radiation after local recurrence. Limited data are available regarding reconservation at LRR. One series of 16 patients who refused salvage mastectomy at LRR after BCT were treated with a second lumpectomy without radiation therapy or chemotherapy. Within this group, 63% were in situ and 37% were invasive recurrences. At 8 years of follow-up evaluation, the diseasefree survival was 69% [56].
Another group of 5 patients were treated with an excisional biopsy procedure alone at LRR. Of these 5 patients, 3 had a noninvasive LRR and were alive without further disease with follow-up periods of .9, 4.0, and 8.5 years. Of the 2 patients with an invasive LRR, 1 patient was alive without further disease at 5.8 years, and 1 patient died of disease .2 years after LRR [20]. Another small series of 8 patients with LRR who refused mastectomy showed that 3 of the 8 patients (37.5%) were alive and free of further failure at a median follow-up period of 76 months [54]. Additional breast conservation surgery may be considered for patients without previous radiation therapy at BCT or DCIS with favorable histologic features, and wide surgical margins, or in the setting of a clinical trial. Axillary surgery Assessment of the axillary status should be performed for an invasive LRR of the breast or an axillary recurrence. Previous breast or axillary surgery is no longer considered a contraindication to sentinel lymph node biopsy (SLNB). At Memorial Sloan Kettering Cancer Center, 3,490 consecutive SLNB procedures for breast cancer were performed, 32 (1%) of which were performed after previous axillary surgery. Of these 32 patients, 22 (69%) patients had sustained breast recurrence after SLNB or axillary lymph node dissection, 7 (22%) patients were performed after a recent failed SLNB or inadequate axillary lymph node dissection, and 3 (9%) patients had undergone earlier axillary surgery for an unrelated condition. Sentinel lymph nodes were identified in 75% of the cases in which previous axillary surgery had been performed. Success was greater when fewer than 10 nodes had been removed at initial surgery [57]. Thus, axillary status at the time of LRR may be performed using a SLNB, or formal axillary lymph node dissection if the SLNB is contraindicated. Adjuvant therapy Adjuvant chemotherapy or hormonal therapy, although controversial, should be considered in patients with a substantial chance of developing metastatic disease. This group includes patients with positive axillary lymph nodes, diffuse disease, or a large tumor size at LRR. Some of these patients may be best treated in a protocol setting and not according to standard chemotherapy guidelines.
Prognosis With Local Recurrence In contrast to chest wall recurrence after mastectomy in which the incidence of simultaneous metastatic disease is between 25% and 50%, LRR after BCT typically is not associated with distant metastases [11,34]. The overall survival at 5 years for patients with LRR after BCT is between 76% and 92% [13,20,55,56]. The median time to second
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relapse after LRR is 97 months, and the median survival time is 103 months [55]. The prognosis at LRR is dependent on several factors, including the size and histologic type of the recurrent tumor, the method of LRR detection, the location of the LRR, the time interval between initial BCT and LRR, and the status of the axillary lymph nodes at both the initial BCT and at LRR. Histologic type of recurrence The histologic type of tumor, specifically whether the LRR is invasive or not, is associated strongly with prognosis [56]. Several series of patients with noninvasive tumors at LRR who were treated with salvage mastectomy showed no local or distant relapses at up to 5 years follow-up evaluation [13,20,54,56]. In patients with an invasive LRR, the overall survival has been shown to range from 52% to 88% [20,56]. Size and stage of local-regional recurrence The majority of invasive LRRs after BCT are detected at an early stage. They are diagnosed as stage I in 51%, stage II in 34%, stage III in 11%, and stage IV in only 3% of cases [21]. Those LRRs measuring ⬍2 cm have an 80% diseasefree survival and a 90% overall survival [17]. Method of detection LRRs detected by mammography alone have a better outcome than those detected by physical examination. The 4-year overall survival was 100% for those noted by mammography, compared with 80% for those found clinically (P ⫽ .043) [20]. Although this may by an independent variable, it is probably another reflection of tumor size. Location of local-regional recurrence Whether or not the LRR is within the same quadrant as the initial tumor does not affect outcome [56]. However, LRRs that are diffuse within the breast, involve the breast skin, or present as an axillary recurrence have a much poorer prognosis than those presenting in breast alone. Patients with LRRs involving skin have a 50% rate of local failure compared with only a 14% failure rate in patients without skin involvement [35]. Skin involvement at LRR increases the incidence of distant metastases from 14% to 44% [14]. It also has been shown that patients with LRR involving skin have a 44% to 83% risk for distant metastases simultaneously or within 2 months of LRR, compared with 5% for those patients without skin involvement at recurrence [54,58]. LRR involving the skin portends a poor overall survival of 13% to 18% between 5 and 10 years after recurrence [14,35]. Axillary recurrence is an uncommon event, representing
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only 2% of LRRs. Patients with axillary recurrence have a 50% incidence of distant disease [59]. Interval to local-regional recurrence The interval from BCT to LRR is an important prognostic indicator in that patients who recur later fare better [11,35,60,61]. Those patients with recurrences within 2 years had a 3-year overall survival of 64% and a 5-year overall survival of 48% [11,60]. In these same studies, recurrences after 5 years yielded an overall survival of 75% to 84% [11,60]. Of those patients presenting with an LRR within 4 years, 50% developed distant metastases, versus only 17% for those presenting after 4 years (P ⬍.01) [61].
Status of Axillary Lymph Nodes The status of the axillary lymph nodes at the initial BCT as well as at the time of the LRR are important prognostic factors [17,35,56,60]. Patients with negative nodes at the primary BCT have an 8% incidence of distant metastases at the LRR, compared with 36% for those with 1 to 3 positive nodes, and 50% for those with 4 of more positive nodes [60]. The status of the axillary lymph nodes at the time of salvage surgery also has an impact on outcome. Patients with negative axillary nodes at salvage surgery have an 87% disease-free survival, those with 1 to 3 nodes have a 72% disease-free survival, and those with 4 or more positive nodes have a 0% disease-free survival [17].
Conclusions The majority of small invasive and noninvasive breast cancers are treated today by BCT, which includes wide local excision with negative surgical margins and radiation treatment to the breast. Studies have shown the incidence of LRR after BCT for stage 0, I, and II patients to range from 5% to 22%. The factors increasing the risk for LRR are positive margins, the presence of high-grade DCIS, young patient age, and the absence of radiation therapy at the time of the initial BCT. Patients who are treated with BCT subsequently should be screened with physical examination, mammography, and perhaps additional imaging techniques such as MRI to detect LRRs at an early stage. Although breast MRI still is controversial in the detection of breast cancer, it may be a useful adjunct in experienced centers to identify breast cancers. Any new finding in a patient with a past medical history of breast cancer should undergo a biopsy examination owing to the high likelihood of recurrent malignancy. The standard treatment for LRR is salvage mastectomy with immediate reconstruction using autologous tissue. There are limited data on reconservation of the breast after
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LRR, although it may be appropriate in selected noninvasive recurrences. Factors that affect prognosis at LRR are invasive versus noninvasive histology, size and stage, method of detection, and breast involvement alone or in addition to skin or axillary involvement. Axillary status of the initial tumor at BCT also may affect prognosis. The prognosis for LRR after BCT is better than chest wall recurrences after mastectomy and patients should be treated with adjuvant chemotherapy and hormonal therapy as indicated by the individual risk for systemic failure.
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[50] Heywang-Kobrunner SH, Schlegel A, Beck R. Contrast enhanced MRI of the breast after limited surgery and radiation therapy. J Comput Assist Tomogr 1993;17:891–900. [51] Weinreb JC, Newstead G. MR imaging of the breast. Radiology 1995;196:593– 610. [52] Solin LJ, Fowble BL, Troupin RH, et al. Biopsy results of new calcification in the postirradiated breast. Cancer 1989;63:1956 – 61. [53] Osborne MP. Salvage mastectomy. Semin Surg Oncol 1991;7:291–95. [54] Recht A, Schnitt SJ, Connolly JL, et al. Prognosis following local or regional recurrence after conservative surgery and radiotherapy for early stage breast carcinoma. Int J Radiat Oncol Biol Phys 1989;16:3–9. [55] Osborne MP, Borgen PI, Wong GY, et al. Salvage mastectomy for local and regional recurrence after breast conserving operation and radiation therapy. Surg Gynecol Obstet 1992;174:189 –94. [56] Abner AL, Recht A, Eberlein T, et al. Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 1993;11:44 – 8. [57] Port ER, Fey J, Gemingnani ML, et al. Reoperative sentinel lymph node biopsy: A new option for patients with primary or locally recurrent breast carcinoma. J Am Coll Surg 2002;195:167–172. [58] Gage I, Schnitt SJ, Recht A, et al. Skin recurrences after breast conserving therapy for early stage breast cancer. J Clin Oncol 1998;16:480 – 486. [59] Newman LA, Hunt KK, Buchholz TA, et al. Presentation, management and outcome of axillary recurrence from breast cancer. Am J Surg 2000;180:252– 6. [60] Kurtz J, Spitalier J, Amalric R. The prognostic significance of late local recurrence after breast-conserving therapy. Int J Radiat Oncol Biol Phys 1990;18:87. [61] Haffty BG, Reiss M, Beinfield M, et al. Ipsilateral breast tumor recurrence as a predictor of distant disease: Implications for systemic therapy at the time of local relapse. J Clin Oncol 1996;14:52–57.
Review
Locally recurrent breast cancer after conservation therapy Tara L. Huston, M.D., Rache M. Simmons, M.D.* Department of Surgery, The Weill Medical College of Cornell University, The New York-Presbyterian Hospital, 425 E. 61st St., 8th Floor, New York, NY 10021, USA Manuscript received January 30, 2004; revised manuscript July 16, 2004
Abstract Background: Today, the majority of small invasive and noninvasive breast cancers are treated with breast conservation therapy (BCT). The incidence of local-regional recurrence (LRR) after BCT for stage 0, I, and II patients ranges between 5% and 22%. Methods: A literature search for BCT, local recurrence, and regional recurrence was performed. Data from over 50 articles pertaining to the characteristics, risk factors, detection, management, and prognosis of these patients with LRR after BCT were collected and analyzed. Results: Positive margins, high-grade ductal carcinoma in situ (DCIS), young age, and the absence of radiation therapy after BCT increase the risk for LRR. Prognosis at LRR is impacted by invasive versus noninvasive histology, size and stage, method of detection, and involvement of skin and/or axillary lymph nodes. The standard treatment is salvage mastectomy. Conclusions: The prognosis for LRR after BCT is favorable compared with patients with postmastectomy chest wall recurrence. © 2005 Excerpta Medica Inc. All rights reserved. Keywords: Breast cancer; Breast conservation therapy; Local recurrence; Regional recurrence
The majority of small invasive and noninvasive breast cancers are treated today by breast conservation therapy (BCT), which includes wide local excision and radiation treatment to the breast. Multiple prospective randomized clinical trials, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04, B-06, and B-17 trials, and the Milan Institute Quandrantectomy versus Radical Mastectomy trial, showed no statistically significant difference in patient survival with mastectomy and breast conservation for small invasive and noninvasive carcinomas [1–10]. The incidence of local-regional recurrence (LRR) after BCT for stage 0, I, and II patients ranges between 5% and 22% [3,7,9,11]. The characteristics, risk factors, detection, management, and prognosis of patients with LRR after BCT are discussed in this collective review.
Characteristics of Local-Regional Recurrences Although all LRR after BCT generally are grouped together, it is important to appreciate that there are several * Corresponding author. Tel.: ⫹1-212-821-0853; fax: ⫹1-212-8210832. E-mail address: [email protected]
different types of recurrences that may reflect both cause and patient prognosis. The types of LRR are categorized by location of the breast recurrence in comparison with the primary treated breast carcinoma. The most common type of LRR, present in 57% to 88% of patients [11–15], appears at the site of the primary breast cancer and probably represents incomplete resection of the initial carcinoma. The second type, which consists of approximately 22% to 28% of LRRs, is within the same quadrant but not directly at the site of the initial carcinoma. These are hypothesized to represent evolution of multifocal ductal carcinoma in situ (DCIS) since the time of the original surgery. The third type of recurrence is found within a different quadrant from the initial breast cancer. These remote LRRs are found in 10% to 12% of patients and likely represent a new primary breast cancer [12]. The fourth type of LRR is the rare radiation-induced carcinoma within the radiated treatment field of the initial primary carcinoma [12]. The fifth category of LRR is a diffuse or inflammatory recurrence, detected in less than 5% of patients (see Fig. 1) [13]. The majority of patients who sustain LRR do so within 2 years [16,17]. The greater the time interval between the initial diagnosis and the LRR, the more likely it is that the recurrence will be located in a remote area of the breast
0002-9610/05/$ – see front matter © 2005 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2004.07.039
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Fig. 1. Sites/types of LRR after BCT [12]. Adapted with permission.
[11,12,18]. Those patients with LRRs in the vicinity of the original tumor recurred an average of 33 months after BCT, versus those with a LRR in a distant location, who recurred an average of 75 months after BCT [15]. These data suggest a treatment failure with the early recurrences at the original site and the development of a new primary cancer, with the later recurrences in remote areas. LRRs after BCT may be either invasive or in situ carcinoma. For women who initially were treated for invasive carcinoma, about 80% recur with invasive carcinoma, whereas the remainder have a DCIS recurrence [19]. In patients initially treated for DCIS, slightly more than half will recur with invasive breast carcinoma, while slightly less than half will have DCIS [20,21]. A small percentage of both invasive carcinoma and DCIS patients will be found to recur with either invasive lobular carcinoma or angiosarcoma [20].
Factors Associated With Increased Risk for Local Recurrence Margin status One of the most important predictors of increased risk for LRR is pathologic margin status after BCT. Margin status typically is described as negative, close, or positive. Controversy exists in the literature regarding the meaning of a close surgical margin, with definitions ranging from less than 1 cm to less than 1 mm. According to the NSABP, a margin is positive only if tumor cells are present at the inked surface. A close margin requires cancer cells to be within 1 mm of the inked margin and a negative margin implies that there is at least a 1-mm rim of normal parenchyma between the tumor and the margin. Positive margins are focal if observed in 3 or fewer power fields or diffuse if found in more than 3 power fields [22–25]. The majority of data show that close or positive margins result in an increased rate of LRR. In one series of 303 invasive breast cancers treated with BCT, patients with negative surgical margins had a 98% probability of local
control at 10 years versus a probability of only 82% in those patients with close or positive margins (P ⫽ .007). Another study showed that patients with negative final margins had 100% local control versus 78% for those without negative margins (P ⫽ .0001) [23]. These data emphasize the importance of obtaining pathologic tumor-free margins at the time of resection or re-excision to optimize local control. An extensive intraductal component (EIC) within an invasive breast cancer generally indicates a larger subclinical tumor burden and an increased likelihood of microscopically positive margins. When the margins are revised to a negative status, recurrence rates then decrease and become equivalent to women without an extensive EIC. In the presence of an EIC, negative margins strongly are recommended. Because revision of margins is equivalent to initial negative margins, it is important to recognize that these patients are not automatic mastectomy candidates [26]. Additionally, there are data to suggest BCT with a radiation boost to the surgical bed, in patients with a close or focally positive margin, generates equal or similar LRR rates as a negative margin [22,24,27]. Solin et al [22] compared nearly 700 women with invasive breast cancer and negative margins (⬎2 mm), positive margins, close margins (ⱕ2 mm), or unknown margins after BCT. All underwent a similar dose of definitive irradiation. There was no significant difference among the groups for 5-year overall survival, no evidence of disease survival, or relapse-free survival. Park et al [27] showed, with 8 years of follow-up evaluation, the LRR for all patients with positive margins was 18% compared with 7% for those with negative margins. However, the patients with a close (defined here as ⬍1 mm) margin had an equal rate of LRR to those with negative surgical margins. When the positive margins were analyzed further, those with a focally positive margin had an LRR of 14%, in contrast to the 27% LRR rate in those with extensively positive margins [27]. Thus, the actual amount of residual tumor in the excision bed is a significant predictor of increased recurrence. Histology of the primary tumor Pathologic characteristics of the tumor also affect the incidence of local recurrence. For more than 20 years, an EIC has been considered a risk factor for increased recurrence. Vicini et al [28] analyzed over 500 women with stage I or II breast cancer to determine the optimal extent of resection and found that an EIC was associated with a higher recurrence rate. For patients with EIC-positive (EIC⫹) tumors, the larger resections were associated with lower risks for recurrence when compared with the smallervolume resections. However, for women with EIC-negative (EIC⫺) tumors, the risk for recurrence was not influenced by the resection volume. The conclusion was that a generous resection volume is more important for EIC⫹ than for EIC⫺ breast cancers. There are 4 main types of DCIS: papillary, cribiform,
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solid, and comedo. By far, cribiform has been shown to carry the greatest risk for increased recurrence. Microinvasion with DCIS most commonly occurs when the subtype is comedo, especially when the lesion is dense and high grade. Tumor necrosis also is associated with an increased risk for recurrence [29]. In one study looking only at women who initially had DCIS, the pathologic characteristics in 83% of the local recurrences were unfavorable, having comedo subtype DCIS, as well as high nuclear grade for the intraductal and invasive components [30]. Silverstein et al [31,32] showed that nuclear grade and the presence of necrosis identifies a high-risk subgroup of DCIS for LRR. Patient age Whether young age is associated with a higher risk for LRR after breast conservation is controversial, however, several studies do show that younger patients have an increased incidence of LRR [33–38]. One retrospective analysis of 290 women with invasive breast cancer, treated with BCT, were subdivided by age at initial diagnosis. Women in the younger group, less than 35 years of age at initial diagnosis, were found to have higher rates of local recurrence and decreased rates of survival than those in the older age group, who were over age 35 at diagnosis (P ⬍.05). With multivariate analysis, age persisted as a statistically significant risk factor for LRR [39]. Similar results were shown by the Danish Breast Cancer Cooperative Group and the European Organization for Research and Treatment of Cancer, in which patients 35 years of age or younger had a 9.24 times higher risk for developing LRR after BCT than patients older than 60 years of age [40].
Fig. 2. Methods of detection of LRR [20].
BCT was decreased from 26.8% without radiation therapy to 12.1% with radiation therapy (P ⬍.000005) [8]. Likewise, the European Organization for Research and Treatment of Cancer 10853 protocol showed the 4-year LRR was 9% for patients treated with breast radiation after lumpectomy compared with 16% for those treated without radiation (P ⫽ .005) [44]. These results were confirmed by multiple other studies [41,45– 47]. Patients treated solely with local excision and not with adjuvant radiation have a shorter time to LRR [21,42,44]. There are studies showing excision alone may be appropriate in selected patients with DCIS. Patients who may be candidates for excision alone are those with small, lowgrade DCIS and generous, clear surgical margins [47,48].
Detection of Local Recurrence Radiation therapy Because of the potential multicentricity of breast cancer, the addition of radiation treatment to lumpectomy in patients with DCIS and invasive carcinoma generally is recommended. The NSABP B-06 trial evaluated the local recurrence of small invasive tumors with and without radiation after lumpectomy. The patients without radiation had a significantly higher rate of local recurrence [1,4,41]. These data have been substantiated by other series [42]. A retrospective subset analysis of the NSABP B-06 trial evaluated the treatment of DCIS by lumpectomy alone versus lumpectomy plus radiation. This study showed that women treated with lumpectomy alone had a 23% local recurrence rate, whereas only 7% of those who received adjuvant radiation had a local recurrence within a follow-up period of 53 months [43]. Because of the issues raised involving DCIS with the B-06 trial, the NSABP initiated a further trial, the B-17 trial, which randomized women with DCIS to those who would receive excision and radiation versus surgical excision only. The results of this trial showed that the 8-year rate of LRR for DCIS treated with
Patients should be screened for the early detection of LRR by breast imaging and clinical examination. LRRs are detected by mammography alone 42% to 75% of the time, by physical examination alone 10% to 33% of the time, by a combination of the physical examination and mammography in 12% to 25% of the time, and by other imaging techniques such as magnetic resonance imaging (MRI) 5% of the time (Fig. 2) [18,20,42]. Some data suggest that MRI may be a sensitive and specific test, in addition to mammography and physical examination, for the detection of LRR. Drew et al [49] showed a sensitivity of 100% and a specificity of 93% in the detection of LRR after breast conservation using breast MRI. This may be because scarring, distortion, and postsurgical changes in density are better characterized by MRI than by mammogram. MRI has become an increasingly useful clinical adjunct for the detection of recurrent cancer in a breast that already has undergone surgical, radiation, or drug therapy. MRI becomes most accurate for the identification of residual tumor 18 months after the cessation of radiation therapy because it takes about this period of time for areas of
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radiation fibrosis to diminish [50]. MRI is recommended for the detection of recurrence in the post-BCT breast, especially when conventional mammographic imaging is indeterminate or negative yet there is a high clinical suspicion for recurrence [51]. A biopsy examination of new findings on breast imaging or examination is recommended. It has been shown that microcalcifications in the site of the previous site of BCT represent a LRR in 58% of cases [52].
Management of Local Recurrence Unlike chest wall recurrences after mastectomy, LRR after BCT typically is not associated with distant metastases [11,34]. Because it would alter overall treatment decisions, it is reasonable to perform an extent of disease work-up with a computerized tomography scan and bone scan at the time of LRR. Between 5% and 12% of patients will be found to have inoperable disease at the time of diagnosis of LRR [11,53,54]. The treatment of choice for LRR historically has been salvage mastectomy. There are very limited data available on reconservation of the breast at LRR. Salvage mastectomy The generally recommended treatment for locally recurrent breast cancer after breast conservation is salvage mastectomy [12,16,20,53–55]. This procedure is relatively successful in controlling local disease, with the incidence of secondary LRR after salvage mastectomy ranging between 4% and 37% [53–55]. The median time to subsequent failure is 18 months (range, 2– 45 mo) [55]. The rate of secondary recurrence decreases with longer disease-free interval between BCT and first LRR [53–55]. Because of the inelasticity of previously irradiated breast skin, tissue expansion with breast reconstruction often results in a poor cosmetic result, thus an autologous tissue flap is the preferred method for breast reconstruction [12]. Reconservation surgery Some patients refuse salvage mastectomy and desire reconservation of the breast at LRR. For the majority of patients, BCT includes radiation treatment and thus needs to be avoided with reconservation therapy. New technologies are being explored that use localized radiation of the breast and may allow reconservation with additional localized radiation after local recurrence. Limited data are available regarding reconservation at LRR. One series of 16 patients who refused salvage mastectomy at LRR after BCT were treated with a second lumpectomy without radiation therapy or chemotherapy. Within this group, 63% were in situ and 37% were invasive recurrences. At 8 years of follow-up evaluation, the diseasefree survival was 69% [56].
Another group of 5 patients were treated with an excisional biopsy procedure alone at LRR. Of these 5 patients, 3 had a noninvasive LRR and were alive without further disease with follow-up periods of .9, 4.0, and 8.5 years. Of the 2 patients with an invasive LRR, 1 patient was alive without further disease at 5.8 years, and 1 patient died of disease .2 years after LRR [20]. Another small series of 8 patients with LRR who refused mastectomy showed that 3 of the 8 patients (37.5%) were alive and free of further failure at a median follow-up period of 76 months [54]. Additional breast conservation surgery may be considered for patients without previous radiation therapy at BCT or DCIS with favorable histologic features, and wide surgical margins, or in the setting of a clinical trial. Axillary surgery Assessment of the axillary status should be performed for an invasive LRR of the breast or an axillary recurrence. Previous breast or axillary surgery is no longer considered a contraindication to sentinel lymph node biopsy (SLNB). At Memorial Sloan Kettering Cancer Center, 3,490 consecutive SLNB procedures for breast cancer were performed, 32 (1%) of which were performed after previous axillary surgery. Of these 32 patients, 22 (69%) patients had sustained breast recurrence after SLNB or axillary lymph node dissection, 7 (22%) patients were performed after a recent failed SLNB or inadequate axillary lymph node dissection, and 3 (9%) patients had undergone earlier axillary surgery for an unrelated condition. Sentinel lymph nodes were identified in 75% of the cases in which previous axillary surgery had been performed. Success was greater when fewer than 10 nodes had been removed at initial surgery [57]. Thus, axillary status at the time of LRR may be performed using a SLNB, or formal axillary lymph node dissection if the SLNB is contraindicated. Adjuvant therapy Adjuvant chemotherapy or hormonal therapy, although controversial, should be considered in patients with a substantial chance of developing metastatic disease. This group includes patients with positive axillary lymph nodes, diffuse disease, or a large tumor size at LRR. Some of these patients may be best treated in a protocol setting and not according to standard chemotherapy guidelines.
Prognosis With Local Recurrence In contrast to chest wall recurrence after mastectomy in which the incidence of simultaneous metastatic disease is between 25% and 50%, LRR after BCT typically is not associated with distant metastases [11,34]. The overall survival at 5 years for patients with LRR after BCT is between 76% and 92% [13,20,55,56]. The median time to second
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relapse after LRR is 97 months, and the median survival time is 103 months [55]. The prognosis at LRR is dependent on several factors, including the size and histologic type of the recurrent tumor, the method of LRR detection, the location of the LRR, the time interval between initial BCT and LRR, and the status of the axillary lymph nodes at both the initial BCT and at LRR. Histologic type of recurrence The histologic type of tumor, specifically whether the LRR is invasive or not, is associated strongly with prognosis [56]. Several series of patients with noninvasive tumors at LRR who were treated with salvage mastectomy showed no local or distant relapses at up to 5 years follow-up evaluation [13,20,54,56]. In patients with an invasive LRR, the overall survival has been shown to range from 52% to 88% [20,56]. Size and stage of local-regional recurrence The majority of invasive LRRs after BCT are detected at an early stage. They are diagnosed as stage I in 51%, stage II in 34%, stage III in 11%, and stage IV in only 3% of cases [21]. Those LRRs measuring ⬍2 cm have an 80% diseasefree survival and a 90% overall survival [17]. Method of detection LRRs detected by mammography alone have a better outcome than those detected by physical examination. The 4-year overall survival was 100% for those noted by mammography, compared with 80% for those found clinically (P ⫽ .043) [20]. Although this may by an independent variable, it is probably another reflection of tumor size. Location of local-regional recurrence Whether or not the LRR is within the same quadrant as the initial tumor does not affect outcome [56]. However, LRRs that are diffuse within the breast, involve the breast skin, or present as an axillary recurrence have a much poorer prognosis than those presenting in breast alone. Patients with LRRs involving skin have a 50% rate of local failure compared with only a 14% failure rate in patients without skin involvement [35]. Skin involvement at LRR increases the incidence of distant metastases from 14% to 44% [14]. It also has been shown that patients with LRR involving skin have a 44% to 83% risk for distant metastases simultaneously or within 2 months of LRR, compared with 5% for those patients without skin involvement at recurrence [54,58]. LRR involving the skin portends a poor overall survival of 13% to 18% between 5 and 10 years after recurrence [14,35]. Axillary recurrence is an uncommon event, representing
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only 2% of LRRs. Patients with axillary recurrence have a 50% incidence of distant disease [59]. Interval to local-regional recurrence The interval from BCT to LRR is an important prognostic indicator in that patients who recur later fare better [11,35,60,61]. Those patients with recurrences within 2 years had a 3-year overall survival of 64% and a 5-year overall survival of 48% [11,60]. In these same studies, recurrences after 5 years yielded an overall survival of 75% to 84% [11,60]. Of those patients presenting with an LRR within 4 years, 50% developed distant metastases, versus only 17% for those presenting after 4 years (P ⬍.01) [61].
Status of Axillary Lymph Nodes The status of the axillary lymph nodes at the initial BCT as well as at the time of the LRR are important prognostic factors [17,35,56,60]. Patients with negative nodes at the primary BCT have an 8% incidence of distant metastases at the LRR, compared with 36% for those with 1 to 3 positive nodes, and 50% for those with 4 of more positive nodes [60]. The status of the axillary lymph nodes at the time of salvage surgery also has an impact on outcome. Patients with negative axillary nodes at salvage surgery have an 87% disease-free survival, those with 1 to 3 nodes have a 72% disease-free survival, and those with 4 or more positive nodes have a 0% disease-free survival [17].
Conclusions The majority of small invasive and noninvasive breast cancers are treated today by BCT, which includes wide local excision with negative surgical margins and radiation treatment to the breast. Studies have shown the incidence of LRR after BCT for stage 0, I, and II patients to range from 5% to 22%. The factors increasing the risk for LRR are positive margins, the presence of high-grade DCIS, young patient age, and the absence of radiation therapy at the time of the initial BCT. Patients who are treated with BCT subsequently should be screened with physical examination, mammography, and perhaps additional imaging techniques such as MRI to detect LRRs at an early stage. Although breast MRI still is controversial in the detection of breast cancer, it may be a useful adjunct in experienced centers to identify breast cancers. Any new finding in a patient with a past medical history of breast cancer should undergo a biopsy examination owing to the high likelihood of recurrent malignancy. The standard treatment for LRR is salvage mastectomy with immediate reconstruction using autologous tissue. There are limited data on reconservation of the breast after
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LRR, although it may be appropriate in selected noninvasive recurrences. Factors that affect prognosis at LRR are invasive versus noninvasive histology, size and stage, method of detection, and breast involvement alone or in addition to skin or axillary involvement. Axillary status of the initial tumor at BCT also may affect prognosis. The prognosis for LRR after BCT is better than chest wall recurrences after mastectomy and patients should be treated with adjuvant chemotherapy and hormonal therapy as indicated by the individual risk for systemic failure.
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