It is not often that a reviewer agrees entirely with material presented in an article. I find myself in the happy situation of largely agreeing with the basic thrust of this interesting report by Chadha and Axelrod. They begin by describing the increased incidence of breast cancer over the recent decade, but do not mention that since 1990 there has actually been a decreased incidence of breast cancer. In retrospect, it has become clear that the statistical increase in breast cancer during the 1980s was an artifact of extensive mammographic screening, which caught the initial appearance of disease earlier and artificially created a temporary surge of cases that has since abated.
True Incidence of Breast Cancer
One of the lasting problems with this statistical artifact is that the extrapolation of that curve of increased incidence in the 1980s was used to create the estimate that 1 in 8 American women will develop breast cancer. It was assumed that the increased incidence would continue endlessly into the future, and that all women would live to be 100 years oldneither of which is true. Extrapolating from these assumptions, statisticians calculated that 1 in 8 American women would develop breast cancer, clearly a vast overestimate of the disease incidence now or anytime in the future.
1 in 8, or 1 in 20?
The issue of how to adjust that risk estimate to be realistic, now that the incidence is declining, has not been addressed. Clearly, over time, after relatively uniform use of screening mammography is established, the true prevalence and incidence of breast cancer will become clear. At that time, it will become apparent that the average American woman's true risk of developing invasive breast cancer during a normal life span of 85 years will be on the order of 1 in 20 or maybe even 1 in 30. Clearly, in a population of 270 million people (with 135 million women and perhaps 50 million over the age of 40), the annual number of breast cancers of approximately 180,000 indicates that far fewer than 1 in 8 will ever develop invasive breast cancer. It is imperative that we recalculate that 1 in 8 risk estimate soon because it has become inappropriately implanted in the media and in the minds of politicians, public health experts, and physicians and surgeons.
While recognizing the real public health issue of breast cancer, we need to reduce some of the current hysteria surrounding it, particularly when widespread use of mammography has led to far earlier disease presentation, a rapidly declining death rate,[4,5] and a far better prognosis. As a matter of fact, we now have the ability to prevent invasive breast cancer by being able to detect ductal carcinoma in situ (DCIS) and excise it before invasion can occur, just as removing colon polyps prevents colon cancer.
A Counterintuitive Conclusion
As the authors note, there is ample evidence that modifications of lymph node dissection or even the avoidance of lymph node dissection[7,8] does not affect overall survival. Those data, of course, lead to the conclusion that lymph node metastases do not govern survival, since whether you do or do not remove nodes, the outcome is the same.[6,7,8] This conclusion is counterintuitive, but nevertheless real, and is amply documented by the long-term results from the National Surgical Adjuvant Breast Project (NSABP) B-04 trial. Despite this evidence, the authors make the assumption early in their article that removal of lymph node metastases is a therapeutic endeavor.
We feel that lymph node metastases are indicators not governors of outcome in breast cancer, just as they are in melanoma and other human cancers. Removal of a nonpalpable, but metastatically involved lymph node is not therapeutic since it does not change the patients outcome. Node removal serves only as an indicator of the potential risk of systemic disease and may lead to initiation of systemic adjuvant therapy to reduce that risk. However, by itself, node removal performs no therapeutic goal. If a lymph node is palpable and involved with metastases, then its removal might be considered therapeutic since it eliminates a palpable mass. However, that is the extent of the therapeutic effectiveness of lymph node removal.
Role of the Sentinel Node
The authors note that more recently the concept of the sentinel node as the entrance point of lymphatic flow to the regional node basin has become thoroughly established by both Giuliano et al, and Alex and Krag. In his latest report, Turner et al of Giulianos group reports finding only a single micrometastasis in one axillary node out of 1,087 nodes retrieved via axillary dissection in 60 women whose sentinel node had been negative by hematoxylin and eosin and histochemical staining. This nails down the concept of the sentinel node as the entrance to the regional lymph node basin. Thus, if the sentinel node is negative by either routine or extensive histologic examination, the chance that another axillary node is positive is extremely remote (1 out of 1,087). With such thorough proof of the anatomic rationale that the sentinel node accurately represents the status of the node basin, the principal reason for removing axillary lymph nodes is eliminated. Thus, analysis of the sentinel lymph node is a surrogate for the status of the lymph node basin.
A Major Impediment
The major impediment to the complete replacement of axillary dissection by sentinel node biopsy is the rigid staging requirements for lymph nodes of the American Joint Committee in Cancer (AJCC), which necessitate removal by dissection in order to establish the N characterization of the TNM staging. However, it is very clear that any staging system should serve the needs of the patient; the patient should not be forced to serve the arbitrary needs of the staging system. All that physicians need to know, at present, is whether lymph nodes in the axilla are positive or negative. The assumption that determining the exact number of affected lymph nodes in the axilla is necessary in order to institute more sophisticated differentiated chemotherapy regimens is based on postulation, not data. There are no current data indicating that better patient survival is achieved with more complicated chemotherapeutic regimens or bone marrow transplantation compared to that achieved by the usual adjuvant CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil)) multidrug chemotherapy. In postmenopausal patients, only one standard adjuvant therapy, tamoxifen(Drug information on tamoxifen) (Nolvadex), is employed, so that there would be no differential therapeutic maneuvers affected by the number of lymph node metastases.
If, for clinical research purposes, knowing the exact number of lymph node metastases is necessary for assignment to specific protocols, then axillary dissection can be confined to those who are node positive with macrometastases established by sentinel node biopsy.
A Logical Sequence
As the authors state, such a policy would eliminate 60% to 70% of axillary dissections. Major conservative modifications of current surgical treatment of breast cancer would be immensely beneficial to patients by reducing morbidity, and to health systems by eliminating unnecessary procedures. As the authors suggest, a logical sequence for patients with breast conservation is that first a sentinel node biopsy be performed. If negative, nothing further need be done; if positive, the patient can immediately receive adjuvant treatment. If an exact node count is necessary, the patient can then have an axillary dissection. At a more sophisticated level, if the sentinel node demonstrates only a micrometastasis, there is no risk that the patient would have extensive nodal disease, and axillary dissection is not needed. Only those with sentinel node macrometastases may need dissection to determine the exact nodal count.
The authors also note that there is low risk of axillary node metastases in those cancers that are 1 cm or smaller in diameter (T1a or T1b), particularly when discovered mammographically, since it has been proven that the incidence of positive nodes in these patients is extremely low, 7% or less. Contrary data from the National Cancer Data Base (NCDB) or the American College of Surgeons registry data show that higher node-positive rates occur when cases have not been reviewed by specific pathologic measurement of the primary cancer. Their estimates of a 15% or higher incidence of positive nodes in T1a or T1b cases cannot be taken at face value, therefore, since in studies of mammographically discovered cancers where the pathology of the primary is carefully reviewed and measured, the incidence of positive lymph nodes in T1a cases is only 3%.[18,19]
Therefore, I agree with Chadha and Axelrods second point that any lymph node dissection, or even sentinel node biopsy, might be completely avoided in T1a and T1b mammographically-discovered breast cancers. Barth et al for instance, pointed out that in T1b mammographically discovered cancers, without high-risk features, the likelihood of an axillary metastasis is only 3%. Thus, 35% of all T1a and T1b cancers have a maximum node- positive rate of only 3% using the most sophisticated contemporary data in cancers that are actually pathologically measured for size.
Truth of An Old Dictum
As Chadha and Alexrod also imply, if primary tumor features such as large size indicate that adjuvant therapy should be done regardless of node status, or if a T1 cancer has lymph vessel invasion (LVI) or poor nuclear grade, the status of the lymph nodes would not alter the decision to utilize adjuvant therapy. Therefore, node removal is unnecessary. This reasoning follows the old medical school dictum: If the results of a test dont change what you do, dont do the test! Because axillary node sampling, biopsy, or dissection is only a test and not a therapy, it can be avoided entirely in those women whose primary tumor features demand the use of adjuvant therapy regardless of node status.
For patients with advanced primary cancers with bulky or palpable axillary lymph node metastases, the treatment of choice today is initial induction chemotherapy, deliberately leaving lymph nodes in place without dissection so as to clinically evaluate their response to treatment.[21,22] Many, if not most, of these patients will have remission or marked reduction of palpable axillary adenopathy and may never need axillary dissection because the regional lymph nodes subsequently receive radiotherapy. Only if the lymph nodes fail to respond to such neoadjuvant chemotherapy, or lymph node metastases recur, do they require surgical removal with axillary dissection.
Chadha and Axelrod have performed a valuable service in bringing to our attention the most contemporary, practical view of the major surgical morbidity of contemporary management of breast canceraxillary dissection. Through reports like this that increase interest in and provide the rationale for avoiding axillary dissection, the next major modification and improvement in breast cancer treatment will be achieved.