Seminars in Surgical Oncology 7:271-277 (1991)
Primary Treatment for Breast Cancer DAVID W. KINNE, MD From the Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
Adequate local-regional treatment of patients with primary operable breast cancer involves controlling multicentric disease in the breast, and axillary dissection to stage the disease and control it in the axilla, when present. Two options, showing equal survival rates in prospective, randomized studies, are breast preservation and mastectomy. In breast preservation, adequate tumor excision with clear histologic margins and axillary dissection is followed by breast irradiation. The mastectomy option involves no radiation therapy and can be followed by reconstruction. Careful selection of patients and detailed description of the pros and cons of each approach should be undertaken on an individual basis. KEY WORDS:local-regional treatment, breast preservation, patient selection
of Rosen et al. [2], who reported residual cancer in 56% of patients. In patients with clinically occult, nonpalpable breast cancers detected on mammography, Schwartz et al. [3] reported a multicentricity incidence of 44%. Of the tumors found to be microinvasive on pathologic examination, 57% were multifocal. In another series from Memorial Sloan-Kettering Cancer Center, 60% of patients in whom mastectomies were performed for in situ cancer had multicentric disease [4]. Thus, even in the earliest, nonpalpable, breast cancers treated, multicentricity is frequently seen upon close examination. Lagios et al. [5] examined mastectomy specimens for cancers with tumor foci outside a 5-cm radius of the reference tumor, the hypothetical border of a breast quadrant. Multifocality was found in 20% of cases. Their findings closely approximated those of Rosen et al. [2], who reported residual tumor in 26% MULTICENTRICITY The incidence of multicentric breast cancer in sites and 38% of patients with reference tumors < 2 cm and distinct from the biopsy site in mastectomy specimens > 2 cm in diameter, respectively. These series analyzed conservative mastectomy is reported to range from 9% to 75% [l]. This wide specimens. A more recent study by Holland et al. [6] discrepancy is caused by variations in three factors: the precision with which multicentricity is defined, the Address reprint requests to Dr. David W. Kline, Breast Service, technique of examination employed, and the extent of Department of Surgery, Memorial Sloan-Kettering Cancer Centissue sampling. When several sections are taken from ter, 1275 York Avenue, New York, NY 10021. article contains material from Kinne DW: The surgical maneach of the three quadrants apart from that containing This agement of primary breast cancer, in “Ca-A Cancer Journal for the cancer, higher rates of multicentricity are reported. Clinicians’’ 41:71-96, 1991, used by permission of J.B. Lippincott This was true in a simulated partial mastectomy series Company.
INTRODUCTION In women with potentially curable breast cancer, with no evidence of distant disease, the goals of surgical treatment are to provide optimal local control, to stage the disease so that patients at high risk of recurrence (who are advised to undertake a course of systemic treatment) can be identified, and to provide the best chance of overall survival. Patients who die of breast cancer have distant occult metastases, indicating either the presence of disease at the time of local treatment, which local-regional treatment cannot affect, or metastases from inadequately treated local or regional disease. In this regard, there are two principal objectives: to control multicentric disease in the breast and to identify and control axillary lymph node metastases.
0 1991 Wiley-Liss, Inc.
272 Kinne
excluded the mastectomy specimens of patients who than 1,200 specimens studied by Rosen et a1 [9]. A were clearly not candidates for breast-sparing proce- progressive spread from a low (I) to a high (11) axillary dures in an attempt to gauge the incidence of multifo- level was noted as the number of positive nodes incal disease left behind if these procedures had been creased. Only 3% of patients had “skip” metastases, performed. Of 399 mastectomy specimens, 3 15 (79‘%1), most of which involved level I1 nodes with negative including specimens from 282 patients with invasive level I nodes. This figure represents 3% of all patients cancers < 5 cm and from 33 patients with noninvasive with axillary metastases. and only 1.6%) of all 1228 cancer, were judged to have been taken from possible patients who had axillary dissection. Fifty percent of candidates for breast preservation and thus were these metastases were limited to level 11; only 0.5‘%, analyzed. Excluded from this series were 84 patients would have had undetected nodal metastases if the who had multifocal tumors (detected clinically or by dissection had included levels I and TI. A close correlamammogram), tumors > 5 cm in diameter or extend- tion exists between the level of nodal involvement and ing to the skin or chest wall, diffuse invasive cancers, the total number of involved nodes. When the highest or clinically and radiographically occult cancers found level of nodal involvement was level I, only 14”/,)of patients had four or more lymph nodes involved. Conon “blind” biopsy. If invasive tumors of 1 2 cm in diameter had been versely. if levels I1 and I11 were involved, 78% and 98%) removed with a margin of 4 cm (representing a quad- of patients. respectively, had more than three nodes rantectomy) in this study, 5% of these patients would affected. One of the controversies in breast cancer managehave been found to harbor invasive tumor foci elsewhere in the breast, and another 5% would have had ment is whether removal of axillary nodal metastases noninvasive cancer detected. However, if these same is a therapeutic practice or merely a staging procedure, tumors had been removed with a 2-cm margin, the permitting identification of patients at high risk of percentage of patients harboring invasive or noninva- recurrence and are therefore candidates for adjuvant sive cancers elsewhere would have increased to 14% systemic treatment. Earlier advocates of the latter hyand 28% respectively. These data indicate that a pothesis believe that axillary node sampling is adequadrantectomy leaves less multicentric disease in the quate and that little therapeutic or staging benefit is remaining breast than does a wide excision with a achieved by thorough axillary dissection [ 101. 2-cm margin. Boova et al. [ 1 I] also studied this problem, evaluating 200 consecutive mastectomy specimens from paAXILLARY LYMPH NODE METASTASES tients who underwent complete axillary dissections. It is recognized that clinical assessment of axillary As in the Memorial series, 60% had no axillary metaslymph node status is associated with a significant inci- tases. Of the 40%) with axillary lymph node involvedence of error. Both false-positive and false-negative ment, seven patients (8.8%) had metastases to levels I1 impressions have been documented by comparison to or 111, or both, if level I was uninvolved pathologipathologic examination of axillary nodes. An error in cally. This figure represents 5.5% of the entire group, clinical evaluation of approximately one-third is indicating that a level I dissection is an accurate prewidely accepted [7]. dictor of the entire axilla in 95% of patients. The pathologic status of the axillary nodes is conThe difficulty in interpreting these studies is that sidered the most important prognostic factor for they are performed in the pathology laboratory on breast cancer patients. In a 30-year follow-up of pa- radical or modified radical mastectomy specimens. Altients undergoing radical mastectomy at Memorial though axillary levels are indicated by the placement Sloan-Kettering Cancer Center, survival was more of tags in the operating room, boundaries between closely correlated with axillary node status than with levels are sometimes indistinct. A study of perhaps the size of the primary cancers [8]. Patients with nega- greater clinical value is the one by Davies et al. [I21 tive nodes had a survival rate of 75%).Involvement of from Guy’s Hospital. These authors compared findthe lower axillary lymph nodes (level I) was associated ings on clinical examination with those obtained on with a survival rate of 40%, and this survival rate axillary node biopsy (done in the operating room). decreased with more advanced axillary nodal disease. those reported on axillary node sampling in the same However. it is likely that the total number of nodes patients, and those derived from complete axillary disinvolved is more important in determining prognosis section. Axillary node biopsy failed to detect metasthan is the level of the axilla at which metastases are tases in 42?4 of patients, and axillary node samplingfound. or excision of nodes in the axillary tail-missed 14% of This theory has been confirmed by a recent analysis the patients with axillary metastases. Even if one beof patterns of axillary lymph node metastases in more lieves that axillary dissection is only a staging proce-
Breast Cancer Primary Treatment 273
dure, it is apparent that a significant number of patients with involved nodes would not be detected by some types of axillary sampling. Axillary lymph nodes are not routinely subjected to serial section, which is a tedious and costly undertaking. In studies of patients with negative axillary nodes in whom serial sectioning of nodes was undertaken, Pickren [13] showed that more than 20% of patients with uninvolved axillary nodes did, indeed, have microscopic metastases in one or more nodes. His findings were later confirmed in another study by Wilkinson et al. [14]. The survival rates for such patients were the same as those for patients with negative nodes. Of importance is the fact that the nodes had been removed, strongly suggesting that these patients benefitted from complete axillary dissection. Most of the studies assessing skip metastases in axillary nodes demonstrate a low risk of metastases to level 111 alone, indicating the efficacy of a level 1-11 dissection if these nodes are pathologically negative. Therefore, a level 1-11 dissection should be adequate for staging purposes and treatment of the axilla if nodes in these levels are negative. An important question, however, is how often will level 111 nodes harbor micrometastases if level I or I1 nodes prove to have microscopic disease despite having been negative clinically at the time of axillary dissection. In the series by Rosen et al. [9], 22% of patients with positive nodes at level 1-11 had involvement of nodes at level 111. Veronesi et al. analyzed distribution of axillary metastases in 539 node-positive patients [15]. The risk of metastases at level 111 was 42.9% if levels I and I1 were involved. If nodes were positive at level I, level 11, and/or level 111 were involved in 41% of cases; this risk was higher with larger primaries and also with a higher number of involved Level I nodes. Veronesi et al. [15] urge complete axillary dissection. These data indicate that a level 1-11 dissection is adequate in patients with negative nodes but that if nodes are positive, a complete dissection is necessary. The biological significance of axillary nodal metastases as predictors of risk of systemic recurrence is not questioned. However, if not detected (or removed), they do not invariably develop into clinically significant lymphadenopathy. In NSABP trial B-04, which was recently updated with 10-year results [16], onethird of patients with breast cancer and clinical negative axillae underwent radical mastectomy. Forty percent had pathologically involved nodes. One-third of patients treated by total mastectomy and observation of the axilla, however, developed clinical disease that was histologically confirmed in the axilla in 17.80/0of cases. It is assumed that the groups are comparable in this randomized, prospective study, indicating that
not all patients with pathologically involved axillary nodes left untreated will develop clinically evident disease in the axilla. Harris and Osteen [17] analyzed B-04 reports and noted that some total mastectomy patients had axillary nodes removed. If the subgroup with no nodes removed is studied separately, 21% developed subsequent axillary metastases. Their analysis also questions whether enough patients were entered into B-04 to prove that axillary dissection did not affect survival. Certainly, axillary dissection can be expected to improve survival in positive-node patients only and not in negative-node patients or positive-node patients who have distant micrometastases. To show a statistically significant improvement in survival from axillary dissection in this small subset of patients, 2,000 patients would be required. On the basis of this and analyses of other studies, Harris and Osteen [ 171 conclude that effective axillary treatment increases the cure rate by 5-10% in breast cancer patients. TREATMENT OPTIONS To achieve these dual objectives of controlling multicentric disease in the breast and identifying and controlling axillary nodal metastases, two principal options for treatment are considered. In a breast-preservation approach, wide excision of the primary (lumpectomy or limited resection) and axillary dissection is complemented with breast irradiation. Alternatively, modified radical mastectomy (or total mastectomy, axillary dissection, and preservation of the pectoralis major muscle), with or without immediate reconstruction, is undertaken. Seldom is postmastectomy irradiation indicated. Selection of candidates for systemic treatment is the same, no matter which local-regional therapy is done. It is generally agreed that the principal objective of breast-preserving surgical techniques in patients with breast cancer is a cosmetic one, designed to retain a cosmetically acceptable breast after complete excision of the tumor. At a consensus conference in 1985, sponsored jointly by Memorial Sloan-Kettering Cancer Center and the Joint Center for Radiation Therapy, a faculty of surgeons and radiotherapists with some experience in breast preservation techniques, along with pathologists and medical oncologists, met to discuss appropriate techniques. There was an attempt to define procedures and to recommend certain techniques and discourage others [ 181. Most surgeons advocate wide excision. A simple excision of the breast primary (or limited resection or partial mastectomy) without regard to margins carries a high risk of local recurrence, and quadrantectomy is
274 Kinne
considered too deforming to permit an acceptable cosmetic result. The terms lumpectomy and segmental mastectomy are imprecise, and their use is discouraged. Lumpectomy has been used by many as an alternative term for wide excision. Axillary dissections also have a variety of definitions. The levels of axillary nodes are defined by the relationship of the nodes to the pectoralis minor muscle. Level I, or the low axilla, are those nodes between the latissimus dorsi muscle (the lateral border of the axilla) and the lateral border of the pectoralis muscle. Level 11, or the mid-axilla, are those nodes behind or deep to the minor muscle. Level 111. or the apex of the axilla, are those nodes medial to the medial border of the pectoralis minor, extending to Halsted’s ligament. Medial to this structure, the vein enters the thorax.
Sampling Sampling is defined as removal of an axillary node or nodes from the lower axilla without definition of precise anatomic boundaries. Low Axillary Dissection Low axillary dissection is an en bloc excision of level 1 of the axilla, from the latissimus dorsi muscle laterally to the lateral border of the pectoralis minor muscle medially, and clearing of the axillary vein superiorly. Level 1-11 Dissection A level I and I1 dissection is an en bloc excision of the low and middle portions of the axilla, which is facilitated by elevation of the pectoralis minor muscle and mobilization of the ipsilateral arm to relax the pectoralis major muscle. This dissection proceeds from the latissimus dorsi muscle laterally to the medial border of the pectoralis minor muscle medially, with clearing of the axillary vein. Full Axillary Dissection (Levels I, 11, 111) Full axillary dissection (levels 1, 11, 111) involves removal of the entire axillary contents, from the latissimus dorsi muscle laterally to the subclavius muscle (Halsted’s ligament) medially, clearing the axillary vein, with preservation or excision of the pectoralis minor muscle. Although these definitions were agreed to at that meeting, a new type of dissection is being carried out for very early lesions, especially those detected by mammography. This may be termed low level I dissection. The low level I nodes are removed from the latissimus dorsi muscle laterally, the pectoralis major muscle medially, but the dissection stops superiorly at the level of the major intercostobrachial nerve, thus
sparing the nerve and not dissecting the axillary vein. Thus, there is no risk of numbness or pain from division of this nerve and no risk for lymphedema of the arm. Indications for this procedure include DCIS with (or even “cannot rule out”) microinvasion on pathological interpretation of the breast lesion. In patients with an invasive breast cancer and a clinically negative axilla, a level I to I1 dissection or a full dissection is the optimal approach. Approximately 25-40”% of the patients so treated will prove to have pathologically involved axillary nodes [ 191; these patients would require radiation therapy to the unremoved higher nodes if a less thorough dissection were done. The combination of some surgery and irradiation to the axilla increases the chances of complications, especially edema of the breast or arm, or both. Should irradiation not eliminate disease in the higher nodes, detection and surgical excision may be difficult. The problem of “skip” metastases in axillary nodes is also a consideration. Whereas only 1% of patients with pathologically negative axillary lymph nodes in levels I and I1 have been shown to have metastases in level III [9). a less thorough axillary dissection that is negative on pathologic examination leaves micrometastases in the higher axillary nodes in 14-24‘%, of patients [12]. For these reasons, dissection of at least levels I to I1 should be done in patients with a clinically negative axilla; for patients with clinically suspicious axillary nodes, a full dissection of the axilla is preferable. Axillary sampling, which helps neither patients nor physicians in planning treatment, is imprecise, both as a term and as a procedure, and should not be used. Higher axillary recurrences have been reported in mastectomy patients undergoing sampling as compared with dissection [20]. The ideal patients for breast-preserving treatment approaches combining surgery and radiation therapy are those with small, peripheral, infiltrating carcinomas and clinically negative axillae who understand what the treatment entails and who desire breast preservation. Several relative contraindications have delineated certain groups of patients who are not well suited for breast preservation. If the relative size of the tumor to the breast is such that complete surgical excision will cause deformity, patients are better advised to undergo mastectomy and to consider subsequent breast reconstruction. Some patients are severely deformed by the surgical procedure. Patients with multiple, palpable cancers in different quadrants of the breast or those with suspicious calcifications detected on mammography in widely separated areas of the breast should be treated by mastectomy. Relative contraindications for breast preservation are patients who are pregnant or elderly and those who pre-
Breast Cancer Primary Treatment TABLE 1. 30-Year Follow-up of 1,458 Patients Undergoing Radical Mastectomy*
# Patients
Status
Alive, free of disease Died of breast cancer Died other causes, free of breast cancer Lost to follow-up
184 826 349 99
* 100 patients developed contralateral primaries.
sent with the following clinical backgrounds: central lesions, with or without Paget’s disease; margins that are involved histologically with carcinoma, especially multifocal intraductal disease; and very large or pendulous breasts. Treatment recommendations should be made after a joint consultation with the surgeon and radiotherapist prior to initiation of therapy. Long-term results after mastectomy have been reported. Robbins and Berg reported 30-year follow-up studies on 1,458 patients treated at Memorial SloanKettering Cancer Center with standard radical mastectomy 1211. Thirteen percent of these women survived for 30 years free of cancer; 57% died of breast cancer, 24% died of other causes, and 7% were lost to follow-up (Table I). Axillary nodal status was a more important determinant of prognosis than was the size of the primary tumor. Patients with tumors less than 2 cm in diameter and involved nodes fared worse than did those with large tumors and negative nodes. Thus, local-regional treatment alone, in an era before systemic therapy, led to cure in a significant number of patients. A supporting view is presented in a paper by Brinkley and Haybittle [22], who studied 704 women who were treated surgically for breast cancer between 1947 and 1950 and who underwent follow-up for 22 years. After 21 years, these investigators observed that the survival curve for these patients paralleled that expected for the normal population. This finding suggested a cure rate of about 18% for all patients with breast cancer and 30% for patients with stage 1 or stage I1 disease. Twenty-five percent of the survivors had axillary metastases, suggesting that some patients with this unfavorable condition were cured by surgery
275
alone and would not have benefitted from systemic therapy. However, the number of patients dying of breast cancer more than 20 years after treatment was 12 times the expected rate in the general population, indicating the long-term risk incurred by patients with this disease. Rutqvist et al. [23] used logarithms of survival times in a study of 14,731 women with breast cancer from Norway. With follow-up periods ranging of 5 to 18 years, the cured fractions were estimated to be 54%, 27%, 19%, and 2% for patients with stages I, 11, 111, and IV disease, respectively. The authors noted that the lognormal model accounted for both a late excess mortality and a cured fraction of patients. Haagensen and Bodian [24] reviewed their 5 1-year personal experience with 1,036 patients treated by radical mastectomy. Results were reported according to the Columbia Clinical Classification system. The local recurrence rate 10 years after radical mastectomy was 3.7% in stage A patients and 12% in stage B patients. Pathologically involved nodes were recovered in 3 1%) of stage A patients, and 28% of stage B patients had pathologically negative nodes. The overall 10-year disease-free survival rate was 77% for patients with negative nodes and 49% for patients with positive nodes. In a retrospective review of patients with small breast cancers treated at Memorial Sloan-Kettering Cancer Center, Rosen et al. [25] showed that patients with pathologic TlNOMO (stage I) disease had a disease-free survival of 84%. It took 12 years before the survival curve flattened, and patients with tumors I:1.O cm in diameter fared better than did those whose cancers measured 1.1-2.0 cm. These findings are confirmed in a 20-year follow-up of these patients [26] (Table 11). Thirty-nine percent of those with the larger tumors who had lymphatic tumor emboli developed distant recurrence. This finding approximates the survival rate of patients with pathologically involved nodes and is an indication for adjuvant systemic therapy when axillary nodes are uninvolved. Patients with stage I1 lesions and pathologically involved nodes have a poorer prognosis than do patients with TlNO disease, again indicating that nodal status
TABLE 11. Recurrence Status of TlNO Breast Carcinoma Patients at End of First and Second Decades of Follow-up*
End of second decade
End of first decade
AWD
Size of primary (cm)
N
Primary Treatment for Breast Cancer DAVID W. KINNE, MD From the Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
Adequate local-regional treatment of patients with primary operable breast cancer involves controlling multicentric disease in the breast, and axillary dissection to stage the disease and control it in the axilla, when present. Two options, showing equal survival rates in prospective, randomized studies, are breast preservation and mastectomy. In breast preservation, adequate tumor excision with clear histologic margins and axillary dissection is followed by breast irradiation. The mastectomy option involves no radiation therapy and can be followed by reconstruction. Careful selection of patients and detailed description of the pros and cons of each approach should be undertaken on an individual basis. KEY WORDS:local-regional treatment, breast preservation, patient selection
of Rosen et al. [2], who reported residual cancer in 56% of patients. In patients with clinically occult, nonpalpable breast cancers detected on mammography, Schwartz et al. [3] reported a multicentricity incidence of 44%. Of the tumors found to be microinvasive on pathologic examination, 57% were multifocal. In another series from Memorial Sloan-Kettering Cancer Center, 60% of patients in whom mastectomies were performed for in situ cancer had multicentric disease [4]. Thus, even in the earliest, nonpalpable, breast cancers treated, multicentricity is frequently seen upon close examination. Lagios et al. [5] examined mastectomy specimens for cancers with tumor foci outside a 5-cm radius of the reference tumor, the hypothetical border of a breast quadrant. Multifocality was found in 20% of cases. Their findings closely approximated those of Rosen et al. [2], who reported residual tumor in 26% MULTICENTRICITY The incidence of multicentric breast cancer in sites and 38% of patients with reference tumors < 2 cm and distinct from the biopsy site in mastectomy specimens > 2 cm in diameter, respectively. These series analyzed conservative mastectomy is reported to range from 9% to 75% [l]. This wide specimens. A more recent study by Holland et al. [6] discrepancy is caused by variations in three factors: the precision with which multicentricity is defined, the Address reprint requests to Dr. David W. Kline, Breast Service, technique of examination employed, and the extent of Department of Surgery, Memorial Sloan-Kettering Cancer Centissue sampling. When several sections are taken from ter, 1275 York Avenue, New York, NY 10021. article contains material from Kinne DW: The surgical maneach of the three quadrants apart from that containing This agement of primary breast cancer, in “Ca-A Cancer Journal for the cancer, higher rates of multicentricity are reported. Clinicians’’ 41:71-96, 1991, used by permission of J.B. Lippincott This was true in a simulated partial mastectomy series Company.
INTRODUCTION In women with potentially curable breast cancer, with no evidence of distant disease, the goals of surgical treatment are to provide optimal local control, to stage the disease so that patients at high risk of recurrence (who are advised to undertake a course of systemic treatment) can be identified, and to provide the best chance of overall survival. Patients who die of breast cancer have distant occult metastases, indicating either the presence of disease at the time of local treatment, which local-regional treatment cannot affect, or metastases from inadequately treated local or regional disease. In this regard, there are two principal objectives: to control multicentric disease in the breast and to identify and control axillary lymph node metastases.
0 1991 Wiley-Liss, Inc.
272 Kinne
excluded the mastectomy specimens of patients who than 1,200 specimens studied by Rosen et a1 [9]. A were clearly not candidates for breast-sparing proce- progressive spread from a low (I) to a high (11) axillary dures in an attempt to gauge the incidence of multifo- level was noted as the number of positive nodes incal disease left behind if these procedures had been creased. Only 3% of patients had “skip” metastases, performed. Of 399 mastectomy specimens, 3 15 (79‘%1), most of which involved level I1 nodes with negative including specimens from 282 patients with invasive level I nodes. This figure represents 3% of all patients cancers < 5 cm and from 33 patients with noninvasive with axillary metastases. and only 1.6%) of all 1228 cancer, were judged to have been taken from possible patients who had axillary dissection. Fifty percent of candidates for breast preservation and thus were these metastases were limited to level 11; only 0.5‘%, analyzed. Excluded from this series were 84 patients would have had undetected nodal metastases if the who had multifocal tumors (detected clinically or by dissection had included levels I and TI. A close correlamammogram), tumors > 5 cm in diameter or extend- tion exists between the level of nodal involvement and ing to the skin or chest wall, diffuse invasive cancers, the total number of involved nodes. When the highest or clinically and radiographically occult cancers found level of nodal involvement was level I, only 14”/,)of patients had four or more lymph nodes involved. Conon “blind” biopsy. If invasive tumors of 1 2 cm in diameter had been versely. if levels I1 and I11 were involved, 78% and 98%) removed with a margin of 4 cm (representing a quad- of patients. respectively, had more than three nodes rantectomy) in this study, 5% of these patients would affected. One of the controversies in breast cancer managehave been found to harbor invasive tumor foci elsewhere in the breast, and another 5% would have had ment is whether removal of axillary nodal metastases noninvasive cancer detected. However, if these same is a therapeutic practice or merely a staging procedure, tumors had been removed with a 2-cm margin, the permitting identification of patients at high risk of percentage of patients harboring invasive or noninva- recurrence and are therefore candidates for adjuvant sive cancers elsewhere would have increased to 14% systemic treatment. Earlier advocates of the latter hyand 28% respectively. These data indicate that a pothesis believe that axillary node sampling is adequadrantectomy leaves less multicentric disease in the quate and that little therapeutic or staging benefit is remaining breast than does a wide excision with a achieved by thorough axillary dissection [ 101. 2-cm margin. Boova et al. [ 1 I] also studied this problem, evaluating 200 consecutive mastectomy specimens from paAXILLARY LYMPH NODE METASTASES tients who underwent complete axillary dissections. It is recognized that clinical assessment of axillary As in the Memorial series, 60% had no axillary metaslymph node status is associated with a significant inci- tases. Of the 40%) with axillary lymph node involvedence of error. Both false-positive and false-negative ment, seven patients (8.8%) had metastases to levels I1 impressions have been documented by comparison to or 111, or both, if level I was uninvolved pathologipathologic examination of axillary nodes. An error in cally. This figure represents 5.5% of the entire group, clinical evaluation of approximately one-third is indicating that a level I dissection is an accurate prewidely accepted [7]. dictor of the entire axilla in 95% of patients. The pathologic status of the axillary nodes is conThe difficulty in interpreting these studies is that sidered the most important prognostic factor for they are performed in the pathology laboratory on breast cancer patients. In a 30-year follow-up of pa- radical or modified radical mastectomy specimens. Altients undergoing radical mastectomy at Memorial though axillary levels are indicated by the placement Sloan-Kettering Cancer Center, survival was more of tags in the operating room, boundaries between closely correlated with axillary node status than with levels are sometimes indistinct. A study of perhaps the size of the primary cancers [8]. Patients with nega- greater clinical value is the one by Davies et al. [I21 tive nodes had a survival rate of 75%).Involvement of from Guy’s Hospital. These authors compared findthe lower axillary lymph nodes (level I) was associated ings on clinical examination with those obtained on with a survival rate of 40%, and this survival rate axillary node biopsy (done in the operating room). decreased with more advanced axillary nodal disease. those reported on axillary node sampling in the same However. it is likely that the total number of nodes patients, and those derived from complete axillary disinvolved is more important in determining prognosis section. Axillary node biopsy failed to detect metasthan is the level of the axilla at which metastases are tases in 42?4 of patients, and axillary node samplingfound. or excision of nodes in the axillary tail-missed 14% of This theory has been confirmed by a recent analysis the patients with axillary metastases. Even if one beof patterns of axillary lymph node metastases in more lieves that axillary dissection is only a staging proce-
Breast Cancer Primary Treatment 273
dure, it is apparent that a significant number of patients with involved nodes would not be detected by some types of axillary sampling. Axillary lymph nodes are not routinely subjected to serial section, which is a tedious and costly undertaking. In studies of patients with negative axillary nodes in whom serial sectioning of nodes was undertaken, Pickren [13] showed that more than 20% of patients with uninvolved axillary nodes did, indeed, have microscopic metastases in one or more nodes. His findings were later confirmed in another study by Wilkinson et al. [14]. The survival rates for such patients were the same as those for patients with negative nodes. Of importance is the fact that the nodes had been removed, strongly suggesting that these patients benefitted from complete axillary dissection. Most of the studies assessing skip metastases in axillary nodes demonstrate a low risk of metastases to level 111 alone, indicating the efficacy of a level 1-11 dissection if these nodes are pathologically negative. Therefore, a level 1-11 dissection should be adequate for staging purposes and treatment of the axilla if nodes in these levels are negative. An important question, however, is how often will level 111 nodes harbor micrometastases if level I or I1 nodes prove to have microscopic disease despite having been negative clinically at the time of axillary dissection. In the series by Rosen et al. [9], 22% of patients with positive nodes at level 1-11 had involvement of nodes at level 111. Veronesi et al. analyzed distribution of axillary metastases in 539 node-positive patients [15]. The risk of metastases at level 111 was 42.9% if levels I and I1 were involved. If nodes were positive at level I, level 11, and/or level 111 were involved in 41% of cases; this risk was higher with larger primaries and also with a higher number of involved Level I nodes. Veronesi et al. [15] urge complete axillary dissection. These data indicate that a level 1-11 dissection is adequate in patients with negative nodes but that if nodes are positive, a complete dissection is necessary. The biological significance of axillary nodal metastases as predictors of risk of systemic recurrence is not questioned. However, if not detected (or removed), they do not invariably develop into clinically significant lymphadenopathy. In NSABP trial B-04, which was recently updated with 10-year results [16], onethird of patients with breast cancer and clinical negative axillae underwent radical mastectomy. Forty percent had pathologically involved nodes. One-third of patients treated by total mastectomy and observation of the axilla, however, developed clinical disease that was histologically confirmed in the axilla in 17.80/0of cases. It is assumed that the groups are comparable in this randomized, prospective study, indicating that
not all patients with pathologically involved axillary nodes left untreated will develop clinically evident disease in the axilla. Harris and Osteen [17] analyzed B-04 reports and noted that some total mastectomy patients had axillary nodes removed. If the subgroup with no nodes removed is studied separately, 21% developed subsequent axillary metastases. Their analysis also questions whether enough patients were entered into B-04 to prove that axillary dissection did not affect survival. Certainly, axillary dissection can be expected to improve survival in positive-node patients only and not in negative-node patients or positive-node patients who have distant micrometastases. To show a statistically significant improvement in survival from axillary dissection in this small subset of patients, 2,000 patients would be required. On the basis of this and analyses of other studies, Harris and Osteen [ 171 conclude that effective axillary treatment increases the cure rate by 5-10% in breast cancer patients. TREATMENT OPTIONS To achieve these dual objectives of controlling multicentric disease in the breast and identifying and controlling axillary nodal metastases, two principal options for treatment are considered. In a breast-preservation approach, wide excision of the primary (lumpectomy or limited resection) and axillary dissection is complemented with breast irradiation. Alternatively, modified radical mastectomy (or total mastectomy, axillary dissection, and preservation of the pectoralis major muscle), with or without immediate reconstruction, is undertaken. Seldom is postmastectomy irradiation indicated. Selection of candidates for systemic treatment is the same, no matter which local-regional therapy is done. It is generally agreed that the principal objective of breast-preserving surgical techniques in patients with breast cancer is a cosmetic one, designed to retain a cosmetically acceptable breast after complete excision of the tumor. At a consensus conference in 1985, sponsored jointly by Memorial Sloan-Kettering Cancer Center and the Joint Center for Radiation Therapy, a faculty of surgeons and radiotherapists with some experience in breast preservation techniques, along with pathologists and medical oncologists, met to discuss appropriate techniques. There was an attempt to define procedures and to recommend certain techniques and discourage others [ 181. Most surgeons advocate wide excision. A simple excision of the breast primary (or limited resection or partial mastectomy) without regard to margins carries a high risk of local recurrence, and quadrantectomy is
274 Kinne
considered too deforming to permit an acceptable cosmetic result. The terms lumpectomy and segmental mastectomy are imprecise, and their use is discouraged. Lumpectomy has been used by many as an alternative term for wide excision. Axillary dissections also have a variety of definitions. The levels of axillary nodes are defined by the relationship of the nodes to the pectoralis minor muscle. Level I, or the low axilla, are those nodes between the latissimus dorsi muscle (the lateral border of the axilla) and the lateral border of the pectoralis muscle. Level 11, or the mid-axilla, are those nodes behind or deep to the minor muscle. Level 111. or the apex of the axilla, are those nodes medial to the medial border of the pectoralis minor, extending to Halsted’s ligament. Medial to this structure, the vein enters the thorax.
Sampling Sampling is defined as removal of an axillary node or nodes from the lower axilla without definition of precise anatomic boundaries. Low Axillary Dissection Low axillary dissection is an en bloc excision of level 1 of the axilla, from the latissimus dorsi muscle laterally to the lateral border of the pectoralis minor muscle medially, and clearing of the axillary vein superiorly. Level 1-11 Dissection A level I and I1 dissection is an en bloc excision of the low and middle portions of the axilla, which is facilitated by elevation of the pectoralis minor muscle and mobilization of the ipsilateral arm to relax the pectoralis major muscle. This dissection proceeds from the latissimus dorsi muscle laterally to the medial border of the pectoralis minor muscle medially, with clearing of the axillary vein. Full Axillary Dissection (Levels I, 11, 111) Full axillary dissection (levels 1, 11, 111) involves removal of the entire axillary contents, from the latissimus dorsi muscle laterally to the subclavius muscle (Halsted’s ligament) medially, clearing the axillary vein, with preservation or excision of the pectoralis minor muscle. Although these definitions were agreed to at that meeting, a new type of dissection is being carried out for very early lesions, especially those detected by mammography. This may be termed low level I dissection. The low level I nodes are removed from the latissimus dorsi muscle laterally, the pectoralis major muscle medially, but the dissection stops superiorly at the level of the major intercostobrachial nerve, thus
sparing the nerve and not dissecting the axillary vein. Thus, there is no risk of numbness or pain from division of this nerve and no risk for lymphedema of the arm. Indications for this procedure include DCIS with (or even “cannot rule out”) microinvasion on pathological interpretation of the breast lesion. In patients with an invasive breast cancer and a clinically negative axilla, a level I to I1 dissection or a full dissection is the optimal approach. Approximately 25-40”% of the patients so treated will prove to have pathologically involved axillary nodes [ 191; these patients would require radiation therapy to the unremoved higher nodes if a less thorough dissection were done. The combination of some surgery and irradiation to the axilla increases the chances of complications, especially edema of the breast or arm, or both. Should irradiation not eliminate disease in the higher nodes, detection and surgical excision may be difficult. The problem of “skip” metastases in axillary nodes is also a consideration. Whereas only 1% of patients with pathologically negative axillary lymph nodes in levels I and I1 have been shown to have metastases in level III [9). a less thorough axillary dissection that is negative on pathologic examination leaves micrometastases in the higher axillary nodes in 14-24‘%, of patients [12]. For these reasons, dissection of at least levels I to I1 should be done in patients with a clinically negative axilla; for patients with clinically suspicious axillary nodes, a full dissection of the axilla is preferable. Axillary sampling, which helps neither patients nor physicians in planning treatment, is imprecise, both as a term and as a procedure, and should not be used. Higher axillary recurrences have been reported in mastectomy patients undergoing sampling as compared with dissection [20]. The ideal patients for breast-preserving treatment approaches combining surgery and radiation therapy are those with small, peripheral, infiltrating carcinomas and clinically negative axillae who understand what the treatment entails and who desire breast preservation. Several relative contraindications have delineated certain groups of patients who are not well suited for breast preservation. If the relative size of the tumor to the breast is such that complete surgical excision will cause deformity, patients are better advised to undergo mastectomy and to consider subsequent breast reconstruction. Some patients are severely deformed by the surgical procedure. Patients with multiple, palpable cancers in different quadrants of the breast or those with suspicious calcifications detected on mammography in widely separated areas of the breast should be treated by mastectomy. Relative contraindications for breast preservation are patients who are pregnant or elderly and those who pre-
Breast Cancer Primary Treatment TABLE 1. 30-Year Follow-up of 1,458 Patients Undergoing Radical Mastectomy*
# Patients
Status
Alive, free of disease Died of breast cancer Died other causes, free of breast cancer Lost to follow-up
184 826 349 99
* 100 patients developed contralateral primaries.
sent with the following clinical backgrounds: central lesions, with or without Paget’s disease; margins that are involved histologically with carcinoma, especially multifocal intraductal disease; and very large or pendulous breasts. Treatment recommendations should be made after a joint consultation with the surgeon and radiotherapist prior to initiation of therapy. Long-term results after mastectomy have been reported. Robbins and Berg reported 30-year follow-up studies on 1,458 patients treated at Memorial SloanKettering Cancer Center with standard radical mastectomy 1211. Thirteen percent of these women survived for 30 years free of cancer; 57% died of breast cancer, 24% died of other causes, and 7% were lost to follow-up (Table I). Axillary nodal status was a more important determinant of prognosis than was the size of the primary tumor. Patients with tumors less than 2 cm in diameter and involved nodes fared worse than did those with large tumors and negative nodes. Thus, local-regional treatment alone, in an era before systemic therapy, led to cure in a significant number of patients. A supporting view is presented in a paper by Brinkley and Haybittle [22], who studied 704 women who were treated surgically for breast cancer between 1947 and 1950 and who underwent follow-up for 22 years. After 21 years, these investigators observed that the survival curve for these patients paralleled that expected for the normal population. This finding suggested a cure rate of about 18% for all patients with breast cancer and 30% for patients with stage 1 or stage I1 disease. Twenty-five percent of the survivors had axillary metastases, suggesting that some patients with this unfavorable condition were cured by surgery
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alone and would not have benefitted from systemic therapy. However, the number of patients dying of breast cancer more than 20 years after treatment was 12 times the expected rate in the general population, indicating the long-term risk incurred by patients with this disease. Rutqvist et al. [23] used logarithms of survival times in a study of 14,731 women with breast cancer from Norway. With follow-up periods ranging of 5 to 18 years, the cured fractions were estimated to be 54%, 27%, 19%, and 2% for patients with stages I, 11, 111, and IV disease, respectively. The authors noted that the lognormal model accounted for both a late excess mortality and a cured fraction of patients. Haagensen and Bodian [24] reviewed their 5 1-year personal experience with 1,036 patients treated by radical mastectomy. Results were reported according to the Columbia Clinical Classification system. The local recurrence rate 10 years after radical mastectomy was 3.7% in stage A patients and 12% in stage B patients. Pathologically involved nodes were recovered in 3 1%) of stage A patients, and 28% of stage B patients had pathologically negative nodes. The overall 10-year disease-free survival rate was 77% for patients with negative nodes and 49% for patients with positive nodes. In a retrospective review of patients with small breast cancers treated at Memorial Sloan-Kettering Cancer Center, Rosen et al. [25] showed that patients with pathologic TlNOMO (stage I) disease had a disease-free survival of 84%. It took 12 years before the survival curve flattened, and patients with tumors I:1.O cm in diameter fared better than did those whose cancers measured 1.1-2.0 cm. These findings are confirmed in a 20-year follow-up of these patients [26] (Table 11). Thirty-nine percent of those with the larger tumors who had lymphatic tumor emboli developed distant recurrence. This finding approximates the survival rate of patients with pathologically involved nodes and is an indication for adjuvant systemic therapy when axillary nodes are uninvolved. Patients with stage I1 lesions and pathologically involved nodes have a poorer prognosis than do patients with TlNO disease, again indicating that nodal status
TABLE 11. Recurrence Status of TlNO Breast Carcinoma Patients at End of First and Second Decades of Follow-up*
End of second decade
End of first decade
AWD
Size of primary (cm)
N
