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Sentinel Nodes: Clinical Trial Data Needed

University of Vermont Burlington, VT
National Cancer Institute Bethesda, MD

To the Editor:We are concerned about the conclusions reached by Giuliano et al¹ that "routine [axillary lymphadenectomy] can be eliminated for patients with histopathologically negative sentinel nodes." The statement seems to be based on a nonrandomized study of a rather small number of cases. Giuliano is widely known and well respected for his contributions to the development of dye-based lymphatic mapping methods. Acceptance of this conclusion, however, may discourage efforts to conduct further critical evaluation through ongoing clinical trials.

There are three important reasons for removing regional nodes in patients with breast cancer:

(1) Staging and prognosis: The sentinel node (SN) procedure seems equivalent to axillary dissection (AD), with 97% accuracy for determining whether regional nodes will be found positive or negative on pathologic examination. However, SN surgery alone does not quantitate the extent of node positivity, and there clearly remain technical and biologic issues regarding false-negative rates. All prognostic information available regarding SN surgery remains inferential, since no prospective study has been completed.

(2) Regional control: AD provides nearly 100% long-term regional control. This is important, as recurrences can result in the death of more than 50% of such patients. There are no long-term data comparing SN surgery to AD in the ability to provide regional control. Regional recurrences, especially if minimal disease is present, may take several years to manifest. Physical examination, used as the end point for the report from Giuliano et al,¹ is an inaccurate method for assessing nodal involvement.

(3) Survival: The impact of AD on survival is controversial. Previously completed randomized studies had insufficient patient accrual, such that a 10% survival difference could have been present and not recognized. There are no long-term data on the impact that SN surgery alone may have on patient survival.

The National Cancer Institute is funding two randomized trials that are open for accrual and that address all of the above questions. The National Surgical Adjuvant Breast and Bowel Project 32 trial will randomize 4,000 patients with pathologically negative nodes (by hematoxylin and eosin staining) to receive SN surgery and AD or SN surgery only. The American College of Surgeons Oncology Group will randomize 2,040 node-positive patients to receive AD or SN surgery only. These large numbers of patients are necessary to achieve the level of certainty required to determine whether SN surgery alone is safe for breast cancer patients.

It is prudent for surgeons to provide patients with accurate and understandable data on what is and is not known regarding the long-term risks and benefits of SN surgery alone in comparison to standard axillary surgery. Although the numbers of patients who will accrue to definitive trials may seem large, they represent only a small fraction of the patients burdened with breast cancer each year in the United States. Before SN biopsy is adopted as a new standard for breast cancer care, these trials need to be completed so that patients can be presented with factual data and make informed decisions.

REFERENCES

1. Giuliano AE, Haigh PI, Brennan MB, et al: Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node–negative breast cancer. J Clin Oncol 18: 2553-2559, 2000[Abstract/Free Full Text]

Response

John Wayne Cancer Institute Santa Monica, CA

In Reply:I agree with some of the comments of Drs Krag, Abrams, and Ashikaga regarding our article "Prospective Observational Study of Sentinel Lymphadenectomy Without Further Axillary Dissection."¹ Their points concerning the rationale for removing regional nodes in patients with breast cancer are similarly stated in the Discussion of our article. I also recognize that physical examination, which was a detection method in our study, is an inaccurate method for assessing breast cancer regional recurrence. However, this method is, in fact, the most widely used assessment, has been used in nearly all studies to date, and continues to be the detection method in most ongoing studies. That there are unknown technical and biologic factors regarding sentinel lymphadenectomy (SLND) we acknowledged in the text. The impact of axillary dissection on survival is controversial, and the impact of SLND is unknown. Our article states, "this series is too small to detect slight differences in survival. Currently, there are no other survival data for patients who do not undergo axillary lymphadenectomy (ALND). ..."

While I agree with the above comments, I take strong issue with the contention that our study "may discourage efforts to conduct further critical evaluation through ongoing clinical trials." First, that was not our intent. Our intent was quite the contrary. Further, we have actually treated patients who have been discouraged from entering sentinel node trials because they were told by their physicians "it is unsafe" to remove just the sentinel node. Our prospective observational study demonstrates for the first time the safety and feasibility of sentinel node biopsy alone in selected cases of breast cancer and therefore supports ongoing trials as safe and worthwhile. Our findings should, in fact, encourage clinicians to enter patients onto such trials. Clinical medicine is often advanced by initial observations at single institutions that are later expanded and confirmed at multiple centers. We have now provided such an initial observation that should serve as the basis for the larger, ongoing, multicenter trials.

I cannot reconcile why Krag, Abrams, and Ashikaga believe we concluded that "routine ALND can be eliminated for patients with histopathologically negative sentinel nodes." I am particularly troubled by their omission of the actual word used in our article, namely, "suggests." This omission alters the tone, meaning, and significance of our study. We were more cautious. The article states several times, including in the conclusion of the abstract, that this study "supports" SLND as a staging alternative for breast cancer and then later that this study "suggests" that routine ALND can be eliminated. On page 2558, the article states that "we cannot exclude the possibility that these patients have subclinical nonsentinel metastases not detected by immunohistochemistry that might become clinically significant in time." The article further acknowledges, "Large multicenter trials are required to answer these issues." The three National Cancer Institute–sponsored ongoing breast cancer sentinel node trials are described in some detail. Such a description of ongoing trials is quite unusual for a scientific communication in a peer-reviewed publication. The article further remarks that we hope the ongoing trials will "definitively answer whether SLND can replace ALND ... ."

Therefore, I cannot agree with Krag, Abrams, and Ashikaga that our article may discourage participation in clinical trials. Although no author can control how a reader "may" react to a given publication, we made every effort to be cautious in our conclusion and encouraged participation in the National Cancer Institute–sponsored ongoing trials with no bias to any one trial. Many of us will continue to work hard to complete these important clinical studies. Regardless, I remain convinced that the results of our prospective observational study suggest that SLND may be an alternative to routine axillary lymph node dissection in some patients with breast cancer. In addition, I think most readers will agree that our study reflects the safety of SLND while promoting the rationale and need for further clinical trials.

REFERENCES

1. Giuliano AE, Haigh PI, Brennan MB, et al: Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node–negative breast cancer. J Clin Oncol 18: 2553-2559, 2000

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