Correspondence
Sentinel-Lymph-Node Biopsy
N Engl J Med 1999; 340:317-319January 28, 1999
- Article
To the Editor:
Krag et al. (Oct. 1 issue)1 present interesting data on the use of probe-guided resection of radioactive sentinel nodes in patients with breast cancer, but they conclude that “the procedure can be technically challenging, and the success rate varies according to the surgeon.” In our opinion, preoperative lymphoscintigraphy can facilitate surgical localization and excision of the sentinel node and increase the detection rate.
Lymphoscintigraphy is a nuclear-medicine procedure that is easy to perform and, in conjunction with the intraoperative gamma probe, has been successfully used primarily in patients with malignant melanoma or breast cancer.2,3 The main advantage of this imaging technique is that it allows accurate preoperative localization of the sentinel node; after scintigraphic images have been obtained, a mark can be made on the skin that corresponds to the first lymph node detected by the gamma camera, thereby indicating precisely where the incision should be made. The use of the gamma probe during surgery then guides dissection, making the node biopsy easier and consistently successful. In most patients, the sentinel node is visible within 30 minutes after the injection, regardless of the size of the radiolabeled particles used, when they are injected subdermally.4 Lymphoscintigraphy is not time-consuming; anterior and lateral views, each obtained within five minutes, are sufficient to identify another 10 percent of sentinel nodes that might have not been detected with the use of a probe survey alone.5
5 ReferencesOrazio Schillaci, M.D.
University of L'Aquila, 67040 L'Aquila, ItalyFrancesco Scopinaro, M.D.
University La Sapienza, 00198 Rome, Italy1
Krag D ,Weaver D ,Ashikaga T , et al. The sentinel node in breast cancer -- a multicenter validation study. N Engl J Med 1998;339:941-946
Full Text | Web of Science | Medline2
Alazraki NP ,Eshima D ,Eshima LA , et al. Lymphoscintigraphy, the sentinel node concept, and the intraoperative gamma probe in melanoma, breast cancer, and other potential cancers. Semin Nucl Med 1997;27:55-67
CrossRef | Web of Science | Medline3
Veronesi U ,Paganelli G ,Galimberti V , et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 1997;349:1864-1867
CrossRef | Web of Science | Medline4
De Cicco C ,Cremonesi M ,Chinol M , et al. Optimization of axillary lymphoscintigraphy to detect the sentinel node in breast cancer. Tumori 1997;83:539-541
Web of Science | Medline5
Pijpers R ,Meijer S ,Hoekstra OS , et al. Impact of lymphoscintigraphy on sentinel node identification with technetium-99m-colloidal albumin in breast cancer. J Nucl Med 1997;38:366-368
Web of Science | Medline
To the Editor:
The study by Krag et al. provides much useful information for a woman who must decide between sentinel-node and axillary-node dissection. In assessing the risk of the sentinel-node procedure, she might very well rely on the false negative rate of 11.4 percent, especially since according to newspaper accounts, “the procedure missed cancerous nodes in 13 of 114 women with spreading cancer.”1 The false negative rate is the percentage of all women in the study with positive axillary nodes who would have received a misdiagnosis if they had relied on the sentinel-node procedure. However, I believe that a more relevant measure is the false negative predictive value, which is defined as the complement of the negative predicted value. On the basis of the data reported by Krag et al., the false negative predictive value is 13 of 304, or 4.3 percent. The false negative predictive value is the percentage of all women in the study with negative sentinel nodes who had positive axillary nodes.
Why is the false negative predictive value a better measure of risk than the false negative rate for a woman in whom only the sentinel-node procedure is performed? The false negative rate can be thought of as the risk from a public health point of view. It is the rate of misdiagnosis for women who actually have positive axillary nodes. However, a woman who undergoes only the sentinel-node procedure will not know whether she has positive or negative axillary nodes; she will know only whether she has positive or negative sentinel nodes. Thus, the false negative predictive value can be thought of as the risk from the patient's point of view. It is based only on the information available to the patient at the time (the sentinel-node results), unlike the false negative rate, which is based on information that can become available only later (the true state of the axillary nodes).
1 ReferencesLee R. Abramson, Ph.D.
Nuclear Regulatory Commission, Washington, DC 20555To the Editor:
McMasters et al. (Oct. 1 issue)1 argue that sentinel-node biopsy is “standard practice” in the treatment of melanoma. Excision of a sentinel node is conceptually no different from the elective dissection of a clinically occult regional lymph-node metastasis, a practice that, as the authors note, has been abandoned because it has no benefit in terms of the overall survival of patients with malignant melanoma. The latest World Health Organization (WHO) trial of elective regional lymph-node dissection reports no difference in survival between patients with histologically positive nodes and those with negative nodes.2 It would appear, therefore, that elective lymph-node dissection merely labels patients with occult metastases but has no effect on survival.3 In this case, the argument for sentinel-node biopsy is untenable.
McMasters et al. also argue that the detection of a positive sentinel node may determine the need for adjuvant interferon therapy. Yet, in the Eastern Cooperative Oncology Group EST 1684 trial, treatment with high-dose interferon alfa-2b did not significantly prolong the survival of 34 patients with pathological confirmation of positive metastatic nodes but without clinically apparent evidence of regional lymphadenopathy.4
4 ReferencesSpyros Retsas, M.D.
Charing Cross Hospital, London W6 8RF, United Kingdom1
McMasters KM ,Giuliano AE ,Ross MI , et al. Sentinel-lymph-node biopsy for breast cancer -- not yet the standard of care. N Engl J Med 1998;339:990-995
Full Text | Web of Science | Medline2
Cascinelli N ,Morabito A ,Santinami M ,MacKie RM ,Belli F . Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. Lancet 1998;351:793-796
CrossRef | Web of Science | Medline3
Retsas S . Dissection of regional lymph nodes in cutaneous melanoma. Lancet 1998;351:1884-1884
CrossRef | Web of Science | Medline4
Kirkwood JM ,Strawderman MH ,Ernstoff MS ,Smith TJ ,Borden EC ,Blum RH . Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7-17
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Drs. Schillaci and Scopinaro express the opinion that preoperative lymphoscintigraphy can facilitate surgical localization and excision of the sentinel node, that it is easy to perform and is not time-consuming, and that it may result in the detection of an additional 10 percent of sentinel nodes. These opinions do not appear to be supported by published data. In the study by Pijpers et al. (cited by Schillaci and Scopinaro), all sentinel nodes identified by gamma-camera imaging were retrievable with the gamma probe (not 10 percent fewer than with lymphoscintigraphy).1
According to a recent report, there was a statistically lower rate of sentinel-node identification in patients with breast cancer when a gamma camera was used than when a hand-held probe was used.2 In a series of 113 cases of melanoma, lymphoscintigraphy failed to visualize sentinel nodes in 10 percent of the cases. The gamma probe identified the majority of sentinel nodes that the gamma camera missed.3
Hand-held gamma probes permit close proximity of the detector to radiolabeled sentinel nodes. It may be more challenging to place a gamma camera with a large field of view as close to the radioactive source as a hand-held probe. As predicted by the inverse-square law, hand-held gamma probes perform better than external gamma detectors in detecting deep lesions.4
No technique of sentinel-node identification has been reported to be 100 percent successful. Small-particle tracers are readily absorbed into lymphatics and are therefore better imaging agents. The downside of such tracers is that there is a greater potential for labeling secondary, nonsentinel nodes. Larger particles (e.g., sulfur colloid) are not absorbed as well and are not ideal imaging agents. However, with larger particles, there is generally very good retention in the sentinel node without downstream labeling. This makes sentinel-node identification easier for the surgeon, since the sentinel nodes are generally the only radioactive nodes.
For the moment, there appear to be minimal data in support of the routine use of gamma-camera imaging for sentinel-node surgical procedures in women with breast cancer. However, until the ideal method for the resection of sentinel nodes is developed, continued investigation of any method that can aid detection is warranted.
4 ReferencesDavid N. Krag, M.D.
University of Vermont, Burlington, VT 05405Frederick L. Moffat, Jr., M.D.
University of Miami School of Medicine, Miami, FL 33136Takamaru Ashikaga, Ph.D.
University of Vermont, Burlington, VT 054051
Pijpers R ,Meijer S ,Hoekstra OS , et al. Impact of lymphoscintigraphy on sentinel node identification with technetium-99m-colloidal albumin in breast cancer. J Nucl Med 1997;38:366-368
Web of Science | Medline2
Linehan DC, Hill ADK, Tran KN, et al. Sentinel lymph node localization in breast cancer: unfiltered isotope is superior to filtered. Presented at the Society of Surgical Oncology 51st Annual Cancer Symposium, San Diego, Calif., March 1998. abstract.
3
Krag DN ,Meijer SJ ,Weaver DL , et al. Minimal-access surgery for staging of malignant melanoma. Arch Surg 1995;130:654-658
Web of Science | Medline4
Gulec SA, Moffat FL, Carroll RG. The expanding clinical role for intraoperative gamma probes. In: Freeman LM, ed. Nuclear medicine annual, 1997. Philadelphia: Lippincott-Raven, 1997:209-37.
Author/Editor Response
Four randomized trials have failed to detect an overall survival advantage with the use of elective lymph-node dissection in patients with melanoma, although subgroup analysis reveals a significant survival advantage among some subgroups of patients.1 Retsas's assertion that the detection of microscopically positive lymph nodes has no prognostic importance is based on subgroup analysis of the WHO Melanoma Program trial of elective lymph-node dissection, consisting of 95 patients with negative nodes and 36 with occult positive nodes.2 What Retsas does not mention, however, is that this trial shows a significant difference in survival between patients with occult positive nodes who underwent elective lymph-node dissection and those in whom lymph-node dissection was delayed until clinically detectable nodal metastases developed.
Retsas also concludes that treatment with interferon alfa-2b is ineffective in patients with microscopical evidence of nodal metastases on the basis of a subgroup analysis of a total of 34 patients in the Eastern Cooperative Oncology Group EST 1684 trial.3 This conclusion, again, is based on an inadequate number of patients studied. Subgroup analysis, it appears, is selectively invoked.
Therapeutic lymph-node dissection is curative in some patients. A consistent fraction of patients with nodal metastases have long-term survival without adjuvant therapy. The problem with elective lymph-node dissection is that the majority of patients (the 75 to 80 percent with negative nodes) suffer the morbidity associated with the operation with no potential benefit. Sentinel-lymph-node biopsy allows us to determine nodal status accurately without the morbidity associated with lymphadenectomy.
A recent study of 612 patients with melanoma unequivocally demonstrated that the rates of disease-free and overall survival among patients with microscopically positive sentinel lymph nodes are significantly worse than those among patients with negative sentinel nodes.4 In fact, in multivariate analysis, sentinel-lymph-node status is the strongest predictor of recurrence. Therefore, sentinel-lymph-node biopsy identifies patients most likely to benefit from therapeutic lymph-node dissection and adjuvant therapy — those with nodal metastasis. The value of regional lymphadenectomy and adjuvant interferon alfa-2b therapy for patients with occult nodal metastasis detected by sentinel-lymph-node biopsy is being studied in the ongoing Sunbelt Melanoma Trial.5
Even if sentinel-lymph-node biopsy were shown to have no effect on survival, the value of accurate nodal staging with minimal morbidity would be undeniable. Few physicians or patients would, or should, accept clinical staging of regional lymph nodes when nodal status can be determined accurately by performing a lymph-node biopsy at the time of wide local excision of the melanoma. As the search for more effective adjuvant therapies continues, the ability to determine the nodal stage accurately and thus to study homogeneous patient populations in clinical trials is particularly important.
5 ReferencesKelly M. McMasters, M.D., Ph.D.
Michael J. Edwards, M.D.
University of Louisville, Louisville, KY 40202Merrick I. Ross, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX 770301
Balch CM, Cascinelli N, Sim FH, Soong S-J, Taylor WF, Bufalino R. Elective lymph node dissection: results of prospective randomized surgical trials. In: Balch CM, Houghton AN, Sober AJ, Soong S-J, eds. Cutaneous melanoma. St. Louis: Quality Medical Publishing, 1998:209-25.
2
Cascinelli N ,Morabito A ,Santinami M ,MacKie RM ,Belli F . Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. Lancet 1998;351:793-796
CrossRef | Web of Science | Medline3
Kirkwood JM ,Strawderman MH ,Ernstoff MS ,Smith TJ ,Borden EC ,Blum RH . Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7-17
Web of Science | Medline4
Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol (in press).
5
McMasters KM, Reintgen DS, Edwards MJ, Cerrito P, Krag DN, Ross MI. Sunbelt Melanoma Trial (SMT): a multicenter trial of adjuvant interferon alfa-2b for melanoma patients with early lymph node metastasis detected by lymphatic mapping and sentinel lymph node biopsy. Sunbelt Melanoma Trial Operations Manual. Louisville, Ky.: Sunbelt Melanoma Trial, 1996.
- Citing Articles (2)
