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EDITORIALS |
From the Division of Surgical Oncology, University of Louisville–J. Graham Brown Cancer Center, 315 East Broadway, Louisville, Kentucky.
Correspondence: Address correspondence to Kelly M. McMasters, MD, PhD, Division of Surgical Oncology, University of Louisville–J. Graham Brown Cancer Center, 315 East Broadway, Louisville, KY 40202; Fax: 502-629-3183; E-mail: kelly.mcmasters{at}nortonhealthcare.org
"It is a capital mistake to theorize before one has data. Insensibly one begins to twist facts to suit theories, instead of theories to suit facts." Sherlock Holmes to Dr. Watson, A Scandal in Bohemia. Sir Arthur Conan Doyle.
Few topics have remained as durably controversial as the management of the axillary lymph nodes in breast cancer. In this issue, two reports allow us to reflect once again on the value of axillary lymph node dissection, particularly in light of ongoing clinical trials of sentinel lymph node (SLN) biopsy.
By performing SLN biopsy, about two-thirds of patients avoid having more extensive axillary dissection—because they have negative SLN. For the other one-third of patients with positive SLN, standard treatment is to perform completion lymph node dissection. Although there is no proof that removing these non-sentinel nodes will improve survival, most patients and physicians are loath to leave behind easily resectable disease, especially given the fact that about 37% of patients will have residual axillary nodal metastases detected by routine histopathology.1 Van Zee and colleagues2 from Memorial Sloan-Kettering Cancer Center have constructed a nomogram to determine the likelihood of finding non-sentinel node metastases for patients with positive SLN. After creating the nomogram based on data from 702 patients, they then applied it prospectively to 373 patients to predict the status of the remaining axillary nodes. The implication of this nomogram is obvious—if we can predict the status of the non-sentinel nodes accurately, we can identify patients who may not require completion axillary dissection.
I am old-fashioned about this issue. I still think that, outside of a clinical trial, axillary dissection should be performed for patients with a positive SLN. Although there is little evidence to suggest a survival advantage for axillary dissection, I do not discount completely the possibility that axillary dissection benefits some node-positive patients. Furthermore, the additional staging information (number of positive nodes) obtained from axillary dissection for node-positive patients sometimes alters the adjuvant therapy plan. Finally, I believe that locoregional disease control in the axilla is a laudable aim that is often overlooked. The development of axillary nodal recurrence, an otherwise catastrophic event for patients, is almost completely preventable if axillary dissection is performed for the SLN-positive patients.
The nomogram has good predictive ability across the entire range of patients with positive nodes. It likely can be improved, however, with further prospective testing and more data. As the authors point out, from the existing literature, the two best predictors of non-sentinel node status are the size of the primary tumor and the size of the nodal micrometastases. However, the nomogram does not incorporate the crucial factor of size of nodal metastasis, but rather relies on an indirect measure of this parameter, i.e. the method by which the nodal metastases are detected (routine histology, serial sections, or immunohistochemistry). I think that size of nodal metastasis, which is now included in the new American Joint Committee on Cancer (AJCC) staging system, needs to be incorporated specifically in the nomogram. Furthermore, I do not think it is as important for the nomogram to discriminate between a between a 15% risk and a 50% risk of residual nodal metastases as it is to predict accurately those patients with a very low risk (0 to 5%). These low-risk patients are the ones who reasonably might choose to avoid further axillary surgery. From the data presented, we do not know how good the nomogram is for predicting this very-low-risk population. I suspect there are some loopholes. For instance, according to the nomogram, a patient with a 1 cm, nuclear grade II, estrogen receptor positive tumor, with only a single positive SLN removed that contains a 2 mm metastasis detected by frozen section, has nearly a 40% risk of residual nodal metastasis. Based on other available data, I suspect that the true risk is <5%.3,4
The Memorial nomogram represents significant progress in our understanding of factors predicting more extensive axillary nodal metastasis. My only concern is that this nomogram, which soon will be available to surgeons everywhere in easy-to-use PDA and internet format, may make it far too easy for some surgeons to skip axillary dissection for patients with positive SLN. I do not think we are at the point that the nomogram information should be used for this purpose. Sure, some SLN-positive patients will refuse axillary dissection, and that is their right. The nomogram at least will help quantify their risk of non-sentinel node metastasis so they can make a more informed decision. Until we have results from the American College of Surgeons Oncology Group (ACOSOG) trial Z0011 to guide us in this regard, axillary dissection should be the rule, not the exception, for patients with a positive SLN.
Krag and Single5 would no doubt have little use for the nomogram, because their analysis of the Surveillance, Epidemiology and End Results (SEER) database leads them to believe that axillary dissection improves survival for all subgroups of patients. They divided patients into categories: age groups 40–49 or 50–79, node-negative or node-positive (1 to 3 positive nodes only), and analyzed survival by the number of axillary nodes removed. In these subgroups, survival improves with increasing number of lymph nodes removed. According to the authors, not only does removing a greater number of axillary nodes improve survival for patients with positive lymph nodes, but for patients with negative nodes as well! For node-negative patients with >10 nodes removed, there was an absolute survival benefit of 3% compared to those with fewer nodes removed. This difference was statistically significant only in the postmenopausal age group. For patients with 1–3 positive nodes, removing >10 nodes resulted in an absolute increase in survival of 10% and 11% for the premenopausal and postmenopausal age groups, respectively. Because the database includes over 72,000 patients, the authors are careful to state that statistical significance may not equate to clinical relevance.
How do we interpret these results? Krag and Single believe that they have unearthed new evidence that axillary dissection improves survival. I believe that they have discovered new proof that stage migration is a concept that is poorly understood, and that retrospective subgroup analysis of large databases is fraught with potential error.
In the node-negative patients, a 3% survival advantage for removing more lymph nodes is undoubtedly accounted for by stage migration. The authors do not tell us, but I suspect there is a striking correlation between the number of nodes removed and the presence and number of positive nodes found! The more nodes examined, the more patients will be thrown into the positive node category, and the stages will migrate (much like the migration of the Okies to California in Will Rogers’ time, which improved the average I.Q. of both states). The same explanation likely holds true for the node-positive population. The authors limited their analysis to patients with 1 to 3 positive nodes. Why limit the analysis to this subgroup? All this does is create an artificial category that allows stage migration into the >3 positive node group. It makes more sense to include all patients with positive nodes, or all patients regardless of nodal status. If you look at the survival curves, it is clear that most of the apparent survival decrease is accounted for by the patients who had 1–5 nodes removed. If only 5 lymph nodes are examined, how likely is it that 4 or more will be positive? Because the number of positive nodes is such a strong predictor of survival, this strongly argues for stage migration.
To bolster their case for the therapeutic value of axillary dissection, the authors point to the 10-year follow-up data of the NSABP trial B-04, which demonstrated a 4% survival difference favoring patients who had axillary dissection but which did not reach clinical significance. They fail to mention the more current 25-year follow-up data from this study that show, unequivocally, no survival advantage for axillary dissection.6 The authors claim that the sample size in B-04 is too small to detect small differences in survival. Yet there is no difference to detect–the curves for total mastectomy and radical mastectomy actually intersect at about 20 years follow-up. Increasing the sample size and statistical power will not make differences appear when they do not exist. Krag and Single cite a meta-analysis that suggests a 5.4% survival advantage for axillary dissection when B-04 and five other studies are combined.7 No doubt a repeat meta-analysis, taking into account the longer follow-up of B-04, would result in a lower estimate of potential benefit for axillary dissection.
It is difficult to gaze upon the 25-year survival data from the landmark NSABP B-04 study, then come up with the hypothesis that axillary dissection improves survival—even when the node-positive patients are included. Still, I do not completely discount the possibility that axillary dissection might improve survival in a small fraction of patients. But for a therapy to be effective, the appropriate risk group must be singled out to demonstrate efficacy. If axillary dissection can benefit any patients, they are the ones with positive nodes. There can be no advantage to removing normal lymph nodes. So even if one believes that there is a 5.4% survival advantage for axillary dissection, who believes that this survival advantage would persist if the node-positive patients were excluded? Yet that is exactly what Drs. Krag and Single propose that the SEER data demonstrate. They would have us believe that, through some mystical process, patients with negative SLN have submicroscopic nodal disease, not detectable by pathologists, that spreads systemically and kills them, even though they never develop clinically evident axillary nodal metastases. This is despite the facts that: (1) intensive immunohistochemical analysis of the non-sentinel nodes fails to reveal microscopic nodal metastases when the SLN is negative for tumor,8 (2) SLN biopsy detects at least the same proportion of node-positive patients as axillary dissection,9 and (3) axillary nodal recurrence after a negative SLN biopsy appears to be a very rare event.10–12
This article from Krag and Single is a paper-thin attempt to justify the implausible hypothesis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Trial B-32. This trial is purportedly designed to determine "whether sentinel-node biopsy alone actually reduces the rate of survival when compared with axillary dissection."13 What it really tests, in a convoluted way, is the hypothesis that failure to perform axillary dissection for patients with negative SLN decreases survival. Usually, large randomized trials are based on significant hypothesis-generating data. But where are the data to suggest that axillary dissection benefits the node-negative patients? The authors reach back to retrospective data from 1970 to find support for their hypothesis.14 Even if axillary dissection is associated with a small survival advantage for the node-positive patients, there is no clear justification, without resorting to analysis of data that are explained by stage migration, for the idea that axillary dissection will save the lives of patients with negative nodes. Therefore, the only way there could be a legitimate difference between the randomized treatment arms in the NSABP B-32 study is for the SLN false-negative rate to be so high that it affects survival—and even this is mathematically impossible. While this study will provide important information regarding the prognostic significance of nodal micrometastases, and has been an excellent mechanism for training surgeons to perform SLN biopsy under the auspices of a cooperative group trial, I fear that its ultimate impact will be limited.
So, I hope that clears things up about the axillary lymph nodes in breast cancer. Van Zee and colleagues2 are cautiously optimistic that we can identify some patients with positive SLN who do not need axillary dissection. This issue is being addressed, if accrual can be completed, in ACOSOG trial Z0011. Krag and Single5 tell us that we should perform axillary dissection even for the patients with negative nodes. This issue is being addressed, notwithstanding my concerns expressed above, in NSABP trial B-32. Despite a century of debate, we still are left wondering about the therapeutic value of axillary lymph node dissection in breast cancer.
Received for publication October 15, 2003. Accepted for publication October 21, 2003.
REFERENCES
This article has been cited by other articles:
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  N. Duraker, Z. C. Caynak, and B. Bati Is there any Prognostically Different Subgroup among Patients with Stage IIIC (AnyTN3M0) Breast Carcinoma? Ann. Surg. Oncol., February 1, 2008; 15(2): 430 - 437. [Abstract] [Full Text] [PDF]
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