Reply:
We thank Dr. Twomey for his recent letter endorsing the design of the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).1 Although he challenges our statement that sentinel node biopsy is now a standard of care for patients with primary melanoma, his concerns relate primarily to outcome measures of clinical efficacy. As stated in our paper,2 these measures were not considered in that report on the accuracy and morbidity of the procedure. However, outcome measures based on the third interim analysis of MSLT-I have since been reported in the New England Journal of Medicine.3,4
We caution Dr. Twomey not to conflate elective lymph node dissection and sentinel node biopsy, a common error. Elective lymph node dissection blindly excises clinically normal regional nodes as a prophylactic measure; sentinel node biopsy selectively removes only the most likely nodal target(s) of metastasis. Elective dissection thus carries considerable potential morbidity; sentinel node biopsy does not. Only if careful histopathologic examination of the sentinel node specimen reveals tumor will the patient undergo complete lymphadenectomy. Remember that only about 20% of patients with intermediate-thickness melanoma will have nodal metastases; in clinical trials, the benefit of elective lymph node dissection in this minority was inevitably diluted by its lack of benefit in the remaining ≥80% without nodal metastases.
Interim comparison of the 2 treatment arms of MSLT-I shows that nodal management based on sentinel node status confers a survival benefit: disease-free survival (an endpoint used as a basis for regulatory approval of new cancer drugs5) was significantly higher in patients assigned to wide excision plus sentinel node biopsy than in those assigned to wide excision plus watch-and-wait nodal observation (P = 0.009).3 Moreover, among patients with nodal metastases, the 5-year survival rate was higher for those who underwent immediate lymphadenectomy than for those in whom lymphadenectomy was delayed (72.3% vs. 52.4%, hazard ratio for death 0.51, P = 0.004). MSLT-I data also show the prognostic importance of the sentinel node's tumor status: 5-year survival rate was 90.2% for patients with tumor-negative sentinel nodes compared with 72.3% for patients with tumor-positive sentinel nodes (P ≤ 0.001).3
Dr. Twomey notes a higher incidence of nodal metastases in the sentinel node biopsy group than in the observation group at the time of interim analysis, and he criticizes the “excess rate of node dissection” in the biopsy group. However, it is not accurate to compare the incidence of early (subclinical) metastases and delayed (clinically palpable) metastases because the latter will steadily increase with time. In fact, our recent data indicate that by 10 years the mean projected incidence of nodal metastases in patients with intermediate-thickness melanomas will be 20.5% ± 2.6% (standard error) in the observation group and 20.8% ± 1.7% in the biopsy group.4
Data from interim analysis of MSLT-I provide evidence that occult micrometastases in the sentinel node usually progress to aggressive regional or distant disease. Were this not the case, we would not have seen an overall improvement in disease-free survival among patients assigned to sentinel node biopsy, nor would there have been a significant difference in the rate of nodal relapse between patients with tumor-negative sentinel nodes and those assigned to nodal observation (4% vs. 15.6%, P < 0.001).3 For all patients with nodal metastases identified either by sentinel node biopsy or during observation, the mean number of tumor-involved nodes was only 1.4 in the biopsy group, as compared with 3.3 in the observation group, indicating disease progression in the regional nodal basin during nodal observation. The impact of the sentinel node's tumor status on disease-free and melanoma-specific survival also indicates the aggressive potential of micrometastases in this node (P ≤ 0.001 for both comparisons).
We firmly believe that sentinel node biopsy is the standard of care for staging primary melanomas of intermediate thickness and for treatment planning. Although the standard of care designation is applied to many clinical procedures that do not directly lead to survival benefit,6 our findings indicate that immediate complete lymphadenectomy after identification of a tumor-positive sentinel node improves survival. In patients with primary melanomas that are intermediate in thickness, sentinel node biopsy is preferred to nodal observation.
Donald L. Morton, MD*
Alistair J. Cochran, MD†
John F. Thompson, MD‡
*John Wayne Cancer Institute at Saint John's Health Center Santa Monica, CA
†University of California at Los Angeles Los Angeles, CA
‡Royal Prince Alfred Hospital Camperdown, NSW, Australia
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