Sentinel-Node Technique Will Change the Design of Clinical Trials in Malignant Melanoma

Autor: Judith Manola, Vernon K. Sondak, Brett Coldiron, Lutz Kretschmer, Scott Dinehart, Joseph Ibrahim, Christine Neumann, John M. Kirkwood, Marc S. Ernstoff, Sanjiv S. Agarwala, Merrick K. Ross
Rok vydání: 2002
Předmět:
Zdroj: Journal of Clinical Oncology. 20:2208-2210
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2002.20.8.2208
Popis: To the Editor: Kirkwood et al 1 recently published the results of the intergroup trial E1694, designed to test the efficacy of the GMK ganglioside vaccine versus high-dose interferon alfa-2b (HDI) in malignant melanoma. Analyzing a heterogeneous population of high-risk patients (141 T4N0M0 patients with no lymph node surgery, 56 T4N0M0 patients with negative sentinel nodes, 315 patients with microscopic lymph node metastasis, and 306 patients with clinically detectable node metastasis), they found a minor overall survival benefit for HDI of 5% by 2 years (median duration of follow-up, 16 months). The recurrence-free survival rate was significantly improved by HDI treatment (13% by 2 years). However, only the subset of T4N0M0 patients benefited significantly from HDI treatment. As shown by studies dealing with sentinel-node dissection, 2,3 this group consists of two subpopulations with quite different prognosis: patients with occult micrometastases to their regional lymph nodes and patients with tumor-free regional nodes. The 3-year survival of sentinel-negative T4N0M0 patients was recently observed to be as high as 89.8%. 2 Thus, the inclusion of these patients in trial E1694 is questionable. Moreover, epidermal ulceration has been found to be a significant prognostic factor in T4N0M0 patients with thick primary tumors 2,3 as well as in node-positive patients. 4 Unfortunately, in trial E1684 this feature was not considered in the multivariate analysis. Thus, an alternative interpretation of trial E1684 could be that ulceration or occult regional lymph node involvement were not equally distributed among two therapy groups in the subsets of T4N0M0 patients because of low case numbers in this heterogeneous stratum. Therefore, it would be important to assess the frequency of recurrence to the regional lymph nodes in the T4N0M0 patients who did not receive a sentinel biopsy. If the T4N0M0 patients with HDI fared better because of a lower proportion of recurrences to their regional lymph nodes, a lower proportion of micrometastases to their sentinel nodes at the time of randomization is the most likely explanation. In T4N0M0 patients, the most frequent pathway of first recurrence is locoregional. Because skin and lymph node metastases can be easily treated by surgery with low morbidity, the effect of HDI treatment on the development of visceral metastases and on overall survival seems to be more important. Therefore, a longer duration of follow-up is mandatory to assess the real clinical benefit. In trial E1694, the survival benefit of HDI in node-negative patients was so strong that it outweighed the missing benefit in node-positive patients. Consequently, the authors considered HDI treatment significant for the whole study population. Regarding node-positive patients, some restrictions have to be made as both patients with micro- and macrometastasis were put together in the same strata. However, the clinical stage of the disease (micro- v macrometastases) has been shown to be an independent predictor of survival, besides the number of positive nodes. 5 As illustrated by our own findings, 6 the different time points of diagnosis in patients with micro- and macrometastases result in significantly different survival rates because of the so called lead time bias. In patients with delayed lymph node dissection, we observed an apparent survival benefit of 27.1% by 2 years if the survival rate as calculated from primary tumor excision (when micrometastases are expected to be present) was compared with the survival rate as calculated from the appearance of palpable nodes. Taken together, it would be interesting to know whether the overall survival benefit of HDI for the whole study population holds true in a multifactorial analysis taking into consideration clinical stage, ulceration, the number of positive nodes, Breslow thickness, age, and sex. In conclusion, mixing sentinel node‐negative patients and patients with unknown lymph node status as well as patients with micro- and macrometastasis in the same strata makes it difficult to draw conclusions. In future studies, the regional lymph nodes should be generally staged by sentinel-node biopsy. Moreover, the prognosis of sentinel-negative patients needs further exploration to answer the question if systemic therapies, associated with significant toxicity as HDI, are justified for these patients.
Databáze: OpenAIRE
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