Project 3: New Surgical Approaches for the Management of Malignant Melanoma

特定的目标

SPECIFIC AIMS The specific aims of Project III are to conduct and follow two clinical trials: MSLT-I and MSLT-II. MSLT-I investigates the impact of LM/SLND on survival as well as the prognostic significance of micrometastases detected by histopathologic and molecular techniques (in collaboration with colleagues in Projects I and II). MSLT-II will determine if CLND or observation are clinically equivalent in patients with SLN containing evidence of metastatic melanoma. A.1 Continue a multicenter trial of intraoperative LM/SLND for the management of clinical stage I melanoma (MSLT-I). MSLT-I completed accrual of 2,001 patients, who are now being followed to determine whether there is a survival benefit of LM/SLND and CLND in patients with metastatic melanoma in the SN. Full evaluation of the therapeutic utility of LM/SLND will require an estimated 2-4 years of additional follow up. A.2 Begin a multicenter trial to determine whether LM/SLND and CLND is superior to LM/SLND alone in patients with evidence of metastases in the SNs by histopathological or molecular techniques (MSLT-II). Data derived from previous patients treated with CLND after a histopathologically positive SN demonstrates that 70-80% of these patients will have no additional involved lymph nodes. CLND may not result in clinical benefit for all patients with positive SLN, and its impact on clinical outcomes will be evaluated in a new multicenter, randomized trial, MSLT-II. 1. Appreciation of the microanatomy of the SN and the nonrandom distribution of tumor cells within this node. Earlier data demonstrate that, just as lymph flow is directed into only the SN within a given lymphatic basin, flow is also restricted to certain portions of the SN and not the entire node. Identification of this pertinent portion of the SN may aid the pathologist in assuring that the node is truly sentinel and that the proper area in the node has been examined, decreasing the risk of a false-negative biopsy. MSLT-II will validate the use of carbon particles injected with the blue dye mapping agent in identifying the pertinent segment of the SN. This aim has not yet started due to the inability to obtain GMP quality carbon particles. 2. Development of molecular staging of the SN based upon paraffin-embedded sections. We have previously demonstrated the accuracy and prognostic significance of molecular staging in both fresh frozen and paraffin embedded SN. We have found that 20-30% of histopathologically negative SN will contain molecular evidence of metastasis. These "molecular metastases" are associated with worse overall survival. The molecular assessment of paraffin-embedded SN will be evaluated for validation in MSLT-II. 3. Development of methodology to assay the likelihood of metastases in NSNs. As described in Project I, the risk of NSN metastasis can be estimated. These methods of estimation will be prospectively tested in MSLT-II. A.3 Test the hypothesis that new immunologic and molecular tumor markers can be used to identify subclinical (micrometastatic) melanoma and identify those patients who are at high risk of recurrence after surgical therapy. During the past grant period, the clinical significance of immunologic and molecular tumor markers was demonstrated as a retrospective evaluation of archived specimens. These assays will be tested for validation on prospectively collected specimens from MSLT-I and MSLT-II. A.4 Examine the interaction between tumor burden and endogenous immune response as a determinant of the clinical outcome in melanoma. We have examined lymphatic function in melanoma patients using a novel parameter: uptake of radiocolloid tracer in the SN. Patients undergoing SN mapping receive a pre-operative injection of a radioactive colloid, which at our site is technetium sulfur colloid. The presence of this tracer is identified and quantified during the nodal mapping procedure using a hand-held gamma counter. We are examining prospectively acquired data on patients undergoing lymphatic mapping, and to date, we have analyzed data from 197 patients with tumor-involved SN. This analysis revealed that younger patients (those less than 50} had more radioactivity in the hottest SN than patients older than 50. The figure demonstrates this for both the mean and median with radioactivity measured as a fraction of the radioactivity at the primary injection site (Figure 1). In addition, we found that patients with low relative radioactivity in the SN have a greater chance of harboring metastases in non-SNs on completion lymph node dissection (Figure 2). We have also examined the impact of this measure of nodal function on clinical outcomes. This analysis revealed that patients with relatively "cold" SN demonstrated a strong trend toward worse overall survival than those with "warmer" SN. This difference appears to be manifest primarily in the older patient population, although additional analysis will be needed to adequately examine this issue (Figure 3). We are now performing additional analyses of data from these SN positive patients in order to include a larger number of clinical variables such as basin location, gender, and primary tumor characteristics. We will determine whether SN radioactivity is an independent variable. We are also conducting analyses of patients with negative SNs with regard to their nodal colloid uptake values. In particular, we will perform a matched-pair analysis of patients who had negative SN with subsequent distant metastases to determine if their intraoperative characteristics are significantly different from matched patients without such distant recurrence. We believe this data will provide insights into the function of lymph nodes in tumor surveillance and tumor immunology. It may help explain some paradoxical clinical findings such as the poorer clinical outcomes of older patients with melanoma despite their decreased propensity to develop nodal metastases. These analyses may also provide additional, independently useful criteria for selecting patients more likely to benefit from completion lymph node dissection in the setting of a positive SN. A.5 Determine whether certain morphological changes that indicate immune downregulation of the SN can predict NSN and systemic metastases. Determine whether these morphological changes are reversible with cytokine therapy. The observation that SN is immunosuppressed and uniquely susceptible to initial metastasis may be an important factor in the mechanisms by which a highly immunogenic tumor, such as melanoma, can metastasize. We have determined that certain changes occur in the architecture of interdigitating dendritic cells and other cells in the SN, which suggest immunosuppression. In collaboration with Projects I and II, we will develop correlates of SN architecture and predictive nodals of metastasis either to NSN or to distant sites. These correlates will be prospectively evaluated in MSLT-II.